MAPK/ERK kinase inhibitors

ABSTRACT

Compounds of the following formula are provided for use with MEK: 
                         
wherein the variables are as defined herein. Also provided are pharmaceutical compositions, kits and articles of manufacture comprising such compounds; methods and intermediates useful for making the compounds; and methods of using the presently described compounds.

This is a divisional application of U.S. Ser. No. 12/900,350, filed Oct.7, 2010, which claims benefit of U.S. Ser. No. 11/958,999, filed Dec.18, 2007, which claims the benefit of U.S. Provisional Application No.60/870,913, filed Dec. 20, 2006, which are incorporated herein byreference.

FIELD OF THE INVENTION

The present invention relates to compounds that may be used to inhibitMitogen-Activated Protein kinases (also known as MEK and MAPK/ERKkinases), such as Mitogen-Activated Protein Kinase Kinase 1 (also knownas MAPKK1, MAPK/ERK Kinase 1, and MEK1) and Mitogen-Activated ProteinKinase Kinase 2 (also known as MAPKK2, MAPK/ERK Kinase 2, and MEK2), aswell as compositions of matter, kits and articles of manufacturecomprising these compounds. The invention also relates to methods forinhibiting MEK and/or ERK activity, and treatment methods usingcompounds according to the present invention. In addition, the inventionrelates to methods of making the compounds of the present invention, aswell as intermediates useful in such methods.

BACKGROUND OF THE INVENTION

The mitogen activated protein kinase (MAPK) signaling pathways areinvolved in cellular events such as growth, differentiation and stressresponses (J. Biol. Chem. (1993) 268, 14553-14556). Four parallel MAPKpathways have been identified to date: ERK1/ERK2, JNK, p38 and ERK5.These pathways are linear kinase cascades in that MAPKKK phosphorylatesand activates MAPKK, and MAPKK phosphorylates and activates MAPK. Todate, seven MAPKK homologs (MEK1, MEK2, MKK3, MKK4/SEK, MEK5, MKK6, andMKK7) and four MAPK families (ERK1/2, JNK, p38, and ERK5) have beenidentified. Activation of these pathways regulates the activity of anumber of substrates through phosphorylation. These substrates include:transcription factors such as TCF, c-myc, ATF2 and the AP-1 components,fos and Jun; cell surface components EGF-R; cytosolic componentsincluding PHAS-I, p90^(rsk), cPLA₂ and c-Raf-1; and cytoskeletoncomponents such as tau and MAP2. MAPK signaling cascades are involved incontrolling cellular processes including proliferation, differentiation,apoptosis, and stress responses.

Of the known MAPK signaling pathways, the RAF-MEK-ERK pathway mediatesproliferative and anti-apoptotic signaling from growth factors andoncogenic factors such as Ras and Raf mutant phenotypes that promotetumor growth, progression, and metastasis. By virtue of its central rolein mediating the transmission of growth-promoting signals from multiplegrowth factor receptors, the RAF-MEK-ERK pathway provides moleculartargets with potentially broad therapeutic applications in, for example,cancerous and noon-cancerous hyperproliferative disorders,immunomodulation and inflammation.

MEK occupies a strategic downstream position in the RAF-MEK-ERK pathwaycatalyzing the phosphorylation of its MAPK substrates, ERK1 and ERK2.Anderson et al. “Requirement for integration of signals from twodistinct phosphorylation pathways for activation of MAP kinase.” Nature1990, v. 343, pp. 651-653. In the ERK pathway, MAPKK corresponds withMEK (MAP kinase ERK Kinase) and the MAPK corresponds with ERK(Extracellular Regulated Kinase). No substrates for MEK have beenidentified other than ERK1 and ERK2. Seger et al. “Purification andcharacterization of mitogen-activated protein kinase activator(s) fromepidermal growth factor-stimulated A431 cells.” J. Biol. Chem., 1992, v.267, pp. 14373-14381. This tight selectivity, in addition to the uniqueability to act as a dual-specificity kinase, is consistent with MEK'scentral role in integration of signals into the MAPK pathway. MEK alsoappears to associate strongly with MAP kinase prior to phosphorylatingit, suggesting that phosphorylation of MAP kinase by MEK may require aprior strong interaction between the two proteins. Both this requirementand the unusual specificity of MEK are suggestive that it may haveenough difference in its mechanism of action to other protein kinasesthat selective inhibitors of MEK, possibly operating through allostericmechanisms rather than through the usual blockade of the ATP bindingsite, may be found.

Constitutive action of MAPKs has been reported in >30% of primary tumorcell lines including cell lines derived from colon, lung, breast,pancreas, ovary, and kidney. Hoshino et al. “Constitutive activation ofthe 41-/43-kDa mitogen-activated protein kinase signaling pathway inhuman tumors.” Oncogene, 1999, v. 18, pp. 813-822. Higher concentrationsof active MAPK/ERK (pMAPK/pERK) have been detected in tumor tissue ascompared to normal adjacent tissue. Sivaraman et al. “Hyperexpression ofmitogen-activated protein kinase in human breast cancer.” J. Clin.Invest., 1997, v. 99, pp. 1478-1483.

There is a continued need to find new therapeutic agents to treat humandiseases. The MAPK/ERK kinases, specifically but not limited to MEK1 andMEK2, are especially attractive targets for the discovery of newtherapeutics due to their important role in cancerous hyperproliferativedisorders (e.g., brain, lung, squamous cell, bladder, gastric,pancreatic, breast, head, neck, renal, kidney, ovarian, prostate,colorectal, prostate, colon, epidermoid, esophageal, testicular,gynecological or thyroid cancer; non-cancerous hyperproliferativedisorders (e.g., benign hyperplasia of the skin (e.g., psoriasis),restenosis, and benign prostatic hypertrophy (BPH)); pancreatitis;kidney disease; pain; preventing blastocyte implantation; treatingdiseases related to vasculogenesis or angiogenesis (e.g., tumorangiogenesis, acute and chronic inflammatory disease such as rheumatoidarthritis, atherosclerosis, inflammatory bowel disease, skin diseasessuch as psoriasis, eczema, and scleroderma, diabetes, diabeticretinopathy, retinopathy of prematurity, age-related maculardegeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma andovarian, breast, lung, pancreatic, prostate, colon and epidermoidcancer); asthma; neutrophil chemotaxis; septic shock; T-cell mediateddiseases where immune suppression would be of value (e.g., theprevention of organ transplant rejection, graft versus host disease,lupus erythematosus, multiple sclerosis, and rheumatoid arthritis);conditions where neutrophil influx drives tissue destruction (e.g.,reperfusion injury in myocardial infarction and stroke and inflammatoryarthritis); atherosclerosis; inhibition of keratinocyte responses togrowth factor cocktails; chronic obstructive pulmonary disease (COPD)and other diseases.

SUMMARY OF THE INVENTION

The present invention relates to compounds that have activity forinhibiting MAPK/ERK kinases. The present invention also providescompositions, articles of manufacture and kits comprising thesecompounds, as well as methods for inhibiting MEK and treatment methodsusing compounds according to the present invention. In addition, theinvention relates to methods of making the compounds of the presentinvention, as well as intermediates useful in such methods.

In one embodiment, a pharmaceutical composition is provided thatcomprises a MEK inhibitor according to the present invention as anactive ingredient. Pharmaceutical compositions according to theinvention may optionally comprise 0.001%-100% of one or more inhibitorsof this invention. These pharmaceutical compositions may be administeredor coadministered by a wide variety of routes, including for example,orally, parenterally, intraperitoneally, intravenously, intraarterially,transdermally, sublingually, intramuscularly, rectally, transbuccally,intranasally, liposomally, via inhalation, vaginally, intraoccularly,via local delivery (for example by catheter or stent), subcutaneously,intraadiposally, intraarticularly, or intrathecally. The compositionsmay also be administered or coadministered in slow release dosage forms.

The invention is also directed to kits and other articles of manufacturefor treating disease states associated with MEK.

In one embodiment, a kit is provided that comprises a compositioncomprising at least one MEK inhibitor of the present invention incombination with instructions. The instructions may indicate the diseasestate for which the composition is to be administered, storageinformation, dosing information and/or instructions regarding how toadminister the composition. The kit may also comprise packagingmaterials. The packaging material may comprise a container for housingthe composition. The kit may also optionally comprise additionalcomponents, such as syringes for administration of the composition. Thekit may comprise the composition in single or multiple dose forms.

In another embodiment, an article of manufacture is provided thatcomprises a composition comprising at least one MEK inhibitor of thepresent invention in combination with packaging materials. The packagingmaterial may comprise a container for housing the composition. Thecontainer may optionally comprise a label indicating the disease statefor which the composition is to be administered, storage information,dosing information and/or instructions regarding how to administer thecomposition. The kit may also optionally comprise additional components,such as syringes for administration of the composition. The kit maycomprise the composition in single or multiple dose forms.

Also provided are methods for preparing compounds, compositions and kitsaccording to the present invention. For example, several syntheticschemes are provided herein for synthesizing compounds according to thepresent invention.

Also provided are methods for using compounds, compositions, kits andarticles of manufacture according to the present invention.

In one embodiment, the compounds, compositions, kits and articles ofmanufacture are used to inhibit the activity of MEK and/or ERK. Inparticular, the compounds, compositions, kits and articles ofmanufacture can be used to inhibit the activity of MEK1. In addition,the compounds, compositions, kits and articles of manufacture can beused to inhibit the activity of MEK2. Further, the compounds,compositions, kits and articles of manufacture can be used to inhibitthe activity of ERK1. Also, the compounds, compositions, kits andarticles of manufacture can be used to inhibit the activity of ERK2.

In another embodiment, the compounds, compositions, kits and articles ofmanufacture are used to treat a disease state for which MEK and/or ERKpossess activity that contributes to the pathology and/or symptomologyof the disease state.

In another embodiment, a compound according to the present invention isadministered to a subject wherein MEK and/or ERK activity within thesubject is altered, preferably reduced.

In another embodiment, a prodrug of a compound according to the presentinvention is administered to a subject that is converted to the compoundin vivo where it inhibits MEK and/or ERK.

In another embodiment, a method of inhibiting MEK and/or ERK is providedthat comprises contacting a MEK and/or ERK with a compound according tothe present invention.

In another embodiment, a method of inhibiting MEK and/or ERK is providedthat comprises causing a compound according to the present invention tobe present in a subject in order to inhibit MEK and/or ERK in vivo.

In another embodiment, a method of inhibiting a MEK and/or ERK isprovided that comprises administering a first compound to a subject thatis converted in vivo to a second compound wherein the second compoundinhibits MEK and/or ERK in vivo. It is noted that the compounds of thepresent invention may be the first or second compounds.

In another embodiment, a therapeutic method is provided that comprisesadministering a compound according to the present invention.

In another embodiment, a method is provided for treating a condition ina patient that is known to be mediated by MEK and/or ERK, or which isknown to be treated by MEK inhibitors, the method comprisingadministering to the patient a therapeutically effective amount of acompound according to the present invention.

In another embodiment, a method is provided for treating a disease statefor which MEK and/or ERK possess activity that contributes to thepathology and/or symptomology of the disease state, the methodcomprising: causing a compound according to the present invention to bepresent in a subject in a therapeutically effective amount for thedisease state.

In another embodiment, a method is provided for treating a disease statefor which MEK and/or ERK possess activity that contributes to thepathology and/or symptomology of the disease state, the methodcomprising: administering a first compound to a subject that isconverted in vivo to a second compound such that the second compound ispresent in the subject in a therapeutically effective amount for thedisease state. It is noted that the compounds of the present inventionmay be the first or second compounds.

In another embodiment, a method is provided for treating a disease statefor which MEK and/or ERK possess activity that contributes to thepathology and/or symptomology of the disease state, the methodcomprising: administering a compound according to the present inventionto a subject such that the compound is present in the subject in atherapeutically effective amount for the disease state.

In another embodiment, a method is provided for using a compoundaccording to the present invention in order to manufacture a medicamentfor use in the treatment of a disease state that is known to be mediatedby MEK and/or ERK, or that is known to be treated by MEK inhibitors.

It is noted in regard to all of the above embodiments that the presentinvention is intended to encompass all pharmaceutically acceptableionized forms (e.g., salts) and solvates (e.g., hydrates) of thecompounds, regardless of whether such ionized forms and solvates arespecified since it is well known in the art to administer pharmaceuticalagents in an ionized or solvated form. It is also noted that unless aparticular stereochemistry is specified, recitation of a compound isintended to encompass all possible stereoisomers (e.g., enantiomers ordiastereomers depending on the number of chiral centers), independent ofwhether the compound is present as an individual isomer or a mixture ofisomers. Further, unless otherwise specified, recitation of a compoundis intended to encompass all possible resonance forms and tautomers.With regard to the claims, the language “compound comprising theformula,” “compound having the formula” and “compound of the formula” isintended to encompass the compound and all pharmaceutically acceptableionized forms and solvates, all possible stereoisomers, and all possibleresonance forms and tautomers unless otherwise specifically specified inthe particular claim.

It is further noted that prodrugs may also be administered which arealtered in vivo and become a compound according to the presentinvention. The various methods of using the compounds of the presentinvention are intended, regardless of whether prodrug delivery isspecified, to encompass the administration of a prodrug that isconverted in vivo to a compound according to the present invention. Itis also noted that certain compounds of the present invention may bealtered in vivo prior to inhibit MEK and/or ERK and thus may themselvesbe prodrugs for another compound. Such prodrugs of another compound mayor may not themselves independently have MEK and/or ERK inhibitoryactivity.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-1K illustrate SEQ ID NOS: 1-6 referred to in this application.

DEFINITIONS

Unless otherwise stated, the following terms used in the specificationand claims shall have the following meanings for the purposes of thisApplication.

It is noted that, as used in the specification and the appended claims,the singular forms “a,” “an” and “the” include plural referents unlessthe context clearly dictates otherwise. Further, definitions of standardchemistry terms may be found in reference works, including Carey andSundberg “ADVANCED ORGANIC CHEMISTRY 4^(TH) ED.” Vols. A (2000) and B(2001), Plenum Press, New York. Also, unless otherwise indicated,conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry,biochemistry, recombinant DNA techniques and pharmacology, within theskill of the art are employed.

“Alicyclic” means a moiety comprising a non-aromatic ring structure.Alicyclic moieties may be saturated or partially unsaturated with one,two or more double or triple bonds. Alicyclic moieties may alsooptionally comprise heteroatoms such as nitrogen, oxygen and sulfur. Thenitrogen atoms can be optionally quaternerized or oxidized and thesulfur atoms can be optionally oxidized. Examples of alicyclic moietiesinclude, but are not limited to moieties with (C₃₋₈)rings such ascyclopropyl, cyclohexane, cyclopentane, cyclopentene, cyclopentadiene,cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene,cycloheptadiene, cyclooctane, cyclooctene, and cyclooctadiene.

“Aliphatic” means a moiety characterized by a straight or branched chainarrangement of constituent carbon atoms and may be saturated orpartially unsaturated with one, two or more double or triple bonds.

“Alkenyl” means a straight or branched, carbon chain that contains atleast one carbon-carbon double bond (—CR═CR′— or —CR═CR′R″, wherein R,R′ and R″ are each independently hydrogen or further substituents).Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl,hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and thelike. In particular embodiments, “alkenyl,” either alone or representedalong with another radical, can be a (C₂₋₂₀)alkenyl, a (C₂₋₁₅)alkenyl, a(C₂₋₁₀)alkenyl, a (C₂₋₅)alkenyl or a (C₂₋₃)alkenyl. Alternatively,“alkenyl,” either alone or represented along with another radical, canbe a (C₂)alkenyl, a (C₃)alkenyl or a (C₄)alkenyl.

“Alkenylene” means a straight or branched, divalent carbon chain havingone or more carbon-carbon double bonds (—CR═CR′—, wherein R and R′ areeach independently hydrogen or further substituents). Examples ofalkenylene include ethene-1,2-diyl, propene-1,3-diyl,methylene-1,1-diyl, and the like. In particular embodiments,“alkenylene,” either alone or represented along with another radical,can be a (C₂₋₂₀) alkenylene, a (C₂₋₁₅) alkenylene, a (C₂₋₁₀ alkenylene,a (C₂₋₅) alkenylene or a (C₂₋₃) alkenylene. Alternatively, “alkenylene,”either alone or represented along with another radical, can be a (C₂)alkenylene, a (C₃) alkenylene or a (C₄) alkenylene.

“Alkoxy” means an oxygen moiety having a further alkyl substituent. Thealkoxy groups of the present invention can be optionally substituted.

“Alkyl” represented by itself means a straight or branched, saturated orunsaturated, aliphatic radical having a chain of carbon atoms,optionally with one or more of the carbon atoms being replaced withoxygen (See “oxaalkyl”), a carbonyl group (See “oxoalkyl”), sulfur (See“thioalkyl”), and/or nitrogen (See “azaalkyl”). (C_(X))alkyl and(C_(X-Y))alkyl are typically used where X and Y indicate the number ofcarbon atoms in the chain. For example, (C₁₋₆)alkyl includes alkyls thathave a chain of between 1 and 6 carbons (e.g., methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl,1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl,ethynyl, 1-propynyl, 2-propynyl, and the like). Alkyl represented alongwith another radical (e.g., as in arylalkyl, heteroarylalkyl and thelike) means a straight or branched, saturated or unsaturated aliphaticdivalent radical having the number of atoms indicated or when no atomsare indicated means a bond (e.g., (C₆₋₁₀)aryl(C₁₋₃)alkyl includes,benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl, 2-thienylmethyl,2-pyridinylmethyl and the like). In particular embodiments, “alkyl,”either alone or represented along with another radical, can be a(C₁₋₂₀)alkyl, a (C₁₋₁₅)alkyl, a (C₁₋₁₀)alkyl, a (C₁₋₅)alkyl or a(C₁₋₃)alkyl. Alternatively, “alkyl,” either alone or represented alongwith another radical, can be a (C₁)alkyl, a (C₂)alkyl or a (C₃)alkyl.

“Alkylene”, unless indicated otherwise, means a straight or branched,saturated or unsaturated, aliphatic, divalent radical. (C_(X))alkyleneand (C_(X-Y))alkylene are typically used where X and Y indicate thenumber of carbon atoms in the chain. For example, (C₁₋₆)alkyleneincludes methylene (—CH₂—), ethylene (—CH₂CH₂—), trimethylene(—CH₂CH₂CH₂—), tetramethylene (—CH₂CH₂CH₂CH₂—) 2-butenylene(—CH₂CH═CHCH₂—), 2-methyltetramethylene (—CH₂CH(CH₃)CH₂CH₂—),pentamethylene (—CH₂CH₂CH₂CH₂CH₂—) and the like. In particularembodiments, “alkylene,” either alone or represented along with anotherradical, can be a (C₁₋₂₀)alkylene, a (C₁₋₁₅)alkylene, a (C₁₋₁₀)alkylene,a (C₁₋₅)alkylene or a (C₁₋₃)alkylene. Alternatively, “alkylene,” eitheralone or represented along with another radical, can be a (C₁)alkylene,a (C₂)alkylene or a (C₃)alkylene.

“Alkylidene” means a straight or branched, saturated or unsaturated,aliphatic radical connected to the parent molecule by a double bond.(C_(X))alkylidene and (C_(X-Y))alkylidene are typically used where X andY indicate the number of carbon atoms in the chain. For example,(C₁₋₆)alkylidene includes methylene (═CH₂), ethylidene (═CHCH₃),isopropylidene (═C(CH₃)₂), propylidene (═CHCH₂CH₃), allylidene(═CH—CH═CH₂), and the like. In particular embodiments, “alkylidene,”either alone or represented along with another radical, can be a(C₁₋₂₀)alkylidene, a (C₁₋₁₅)alkylidene, a (C₁₋₁₀)alkylidene, a(C₁₋₅)alkylidene or a (C₁₋₃)alkylidene. Alternatively, “alkylidene,”either alone or represented along with another radical, can be a(C₁)alkylidene, a (C₂)alkylidene or a (C₃)alkylidene.

“Alkynyl” means a straight or branched, carbon chain that contains atleast one carbon-carbon triple bond (—C≡C— or —C≡CR, wherein R ishydrogen or a further substituent). Examples of alkynyl include ethynyl,propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like. In particularembodiments, “alkynyl,” either alone or represented along with anotherradical, can be a (C₂₋₂₀)alkynyl, a (C₂₋₁₅)alkynyl, a (C₂₋₁₀)alkynyl, a(C₂₋₅)alkynyl or a (C₂₋₃)alkynyl. Alternatively, “alkynyl,” either aloneor represented along with another radical, can be a (C₂)alkynyl, a(C₃)alkynyl or a (C₄)alkynyl.

“Alkynylene” means a straight or branched, divalent carbon chain havingone or more carbon-carbon triple bonds (—CR≡CR′—, wherein R and R′ areeach independently hydrogen or further substituents). Examples ofalkynylene include ethyne-1,2-diyl, propyne-1,3-diyl, and the like. Inparticular embodiments, “alkynylene,” either alone or represented alongwith another radical, can be a (C₂₋₂₀) alkynylene, a (C₂₋₁₅) alkynylene,a (C₂₋₁₀) alkynylene, a (C₂₋₅) alkynylene or a (C₂₋₃) alkynylene.Alternatively, “alkynylene,” either alone or represented along withanother radical, can be a (C₂) alkynylene, a (C₃) alkynylene or a (C₄)alkynylene.

“Amido” means the radical —C(═O)—NR—, —C(═O)—NRR′, —NR—C(═O)— and/or—NR—C(═O)R′, wherein each R and R′ are independently hydrogen or afurther substituent.

“Amino” means a nitrogen moiety having two further substituents where,for example, a hydrogen or carbon atom is attached to the nitrogen. Forexample, representative amino groups include —NH₂, —NHCH₃, —N(CH₃)₂,—NH((C₁₋₁₀)alkyl), —N((C₁₋₁₀)alkyl)₂, —NH(aryl), —NH(heteroaryl),—N(aryl)₂, —N(heteroaryl)₂, and the like. Optionally, the twosubstituents together with the nitrogen may also form a ring. Unlessindicated otherwise, the compounds of the invention containing aminomoieties may include protected derivatives thereof. Suitable protectinggroups for amino moieties include acetyl, tert-butoxycarbonyl,benzyloxycarbonyl, and the like.

“Animal” includes humans, non-human mammals (e.g., dogs, cats, rabbits,cattle, horses, sheep, goats, swine, deer, and the like) and non-mammals(e.g., birds, and the like).

“Aromatic” means a moiety wherein the constituent atoms make up anunsaturated ring system, all atoms in the ring system are sp² hybridizedand the total number of pi electrons is equal to 4n+2. An aromatic ringmay be such that the ring atoms are only carbon atoms or may includecarbon and non-carbon atoms (See “heteroaryl”).

“Aryl” means a monocyclic or polycyclic ring assembly wherein each ringis aromatic or when fused with one or more rings forms an aromatic ringassembly. If one or more ring atoms is not carbon (e.g., N, S), the arylis a heteroaryl. (C_(X))aryl and (C_(X-Y))aryl are typically used whereX and Y indicate the number of carbon atoms in the ring. In particularembodiments, “aryl,” either alone or represented along with anotherradical, can be a (C₃₋₁₄)aryl, a (C₃₋₁₀)aryl, a (C₃₋₇)aryl, a(C₈₋₁₀)aryl or a (C₅₋₇)aryl. Alternatively, “aryl,” either alone orrepresented along with another radical, can be a (C₅)aryl, a (C₆)aryl, a(C₇)aryl, a (C₈)aryl, a (C₉)aryl or a (C₁₀)aryl.

“Azaalkyl” and “aminoalkyl” mean an alkyl, as defined above, exceptwhere one or more of the carbon atoms forming the alkyl chain arereplaced with substituted or unsubstituted nitrogen atoms (—NR— or—NRR′, wherein R and R′ are each independently hydrogen or furthersubstituents). For example, a (C₁₋₁₀)azaalkyl refers to a chaincomprising between 1 and 10 carbons and one or more nitrogen atoms.

“Bicycloalkyl” means a saturated or partially unsaturated fused, spiroor bridged bicyclic ring assembly. In particular embodiments,“bicycloalkyl,” either alone or represented along with another radical,can be a (C₄₋₁₅)bicycloalkyl, a (C₄₋₁₀)bicycloalkyl, a(C₆₋₁₀)bicycloalkyl or a (C₈₋₁₀)bicycloalkyl. Alternatively,“bicycloalkyl,” either alone or represented along with another radical,can be a (C₈)bicycloalkyl, a (C₉)bicycloalkyl or a (C₁₀)bicycloalkyl.

“Bicycloaryl” means a fused, spiro or bridged bicyclic ring assemblywherein at least one of the rings comprising the assembly is aromatic.(C_(X))bicycloaryl and (C_(X-Y))bicycloaryl are typically used where Xand Y indicate the number of carbon atoms in the bicyclic ring assemblyand directly attached to the ring. In particular embodiments,“bicycloaryl,” either alone or represented along with another radical,can be a (a (C₄₋₁₅)bicycloaryl, a (C₄₋₁₀)bicycloaryl, a(C₆₋₁₀)bicycloaryl or a (C₈₋₁₀)bicycloaryl. Alternatively,“bicycloalkyl,” either alone or represented along with another radical,can be a (C₈)bicycloaryl, a (C₉)bicycloaryl or a (C₁₀)bicycloaryl.

“Bridging ring” and “bridged ring” as used herein refer to a ring thatis bonded to another ring to form a compound having a bicyclic orpolycyclic structure where two ring atoms that are common to both ringsare not directly bound to each other. Non-exclusive examples of commoncompounds having a bridging ring include borneol, norbornane,7-oxabicyclo[2.2.1]heptane, and the like. One or both rings of thebicyclic system may also comprise heteroatoms.

“Carbamoyl” means the radical —OC(O)NRR′, wherein R and R′ are eachindependently hydrogen or further substituents.

“Carbocycle” means a ring consisting of carbon atoms.

“Carbonyl” means the radical —C(═O)— and/or —C(═O)R, wherein R ishydrogen or a further substituent. It is noted that the carbonyl radicalmay be further substituted with a variety of substituents to formdifferent carbonyl groups including acids, acid halides, aldehydes,amides, esters, and ketones.

“Carboxy” means the radical —C(═O)—O— and/or —C(═O)—OR, wherein R ishydrogen or a further substituent. It is noted that compounds of theinvention containing carboxy moieties may include protected derivativesthereof, i.e., where the oxygen is substituted with a protecting group.Suitable protecting groups for carboxy moieties include benzyl,tert-butyl, and the like.

“Cyano” means the radical —CN.

“Cycloalkyl” means a non-aromatic, saturated or partially unsaturated,monocyclic, bicyclic or polycyclic ring assembly. (C_(X))cycloalkyl and(C_(X-Y))cycloalkyl are typically used where X and Y indicate the numberof carbon atoms in the ring assembly. For example, (C₃₋₁₀)cycloalkylincludes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, adamantan-1-yl,decahydronaphthyl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl,2-oxobicyclo[2.2.1]hept-1-yl, and the like. In particular embodiments,“cycloalkyl,” either alone or represented along with another radical,can be a (C₃₋₁₄)cycloalkyl, a (C₃₋₁₀)cycloalkyl, a (C₃₋₇)cycloalkyl, a(C₈₋₁₀)cycloalkyl or a (C₅₋₇)cycloalkyl. Alternatively, “cycloalkyl,”either alone or represented along with another radical, can be a(C₅)cycloalkyl, a (C₆)cycloalkyl, a (C₇)cycloalkyl, a (C₈)cycloalkyl, a(C₉)cycloalkyl or a (C₁₀)cycloalkyl.

“Cycloalkylene” means a divalent, saturated or partially unsaturated,monocyclic, bicyclic or polycyclic ring assembly. (C_(X))cycloalkyleneand (C_(X-Y))cycloalkylene are typically used where X and Y indicate thenumber of carbon atoms in the ring assembly. In particular embodiments,“cycloalkylene,” either alone or represented along with another radical,can be a (C₃₋₁₄)cycloalkylene, a (C₃₋₁₀)cycloalkylene, a(C₃₋₇)cycloalkylene, a (C₈₋₁₀)cycloalkylene or a (C₅₋₇)cycloalkylene.Alternatively, “cycloalkylene,” either alone or represented along withanother radical, can be a (C₅)cycloalkylene, a (C₆)cycloalkylene, a(C₇)cycloalkylene, a (C₈)cycloalkylene, a (C₉)cycloalkylene or a(C₁₀)cycloalkylene.

“Disease” specifically includes any unhealthy condition of an animal orpart thereof and includes an unhealthy condition that may be caused by,or incident to, medical or veterinary therapy applied to that animal,i.e., the “side effects” of such therapy.

“Fused ring” as used herein refers to a ring that is bonded to anotherring to form a compound having a bicyclic structure where the ring atomsthat are common to both rings are directly bound to each other.Non-exclusive examples of common fused rings include decalin,naphthalene, anthracene, phenanthrene, indole, furan, benzofuran,quinoline, and the like. Compounds having fused ring systems may besaturated, partially saturated, carbocyclics, heterocyclics, aromatics,heteroaromatics, and the like.

“Halo” means fluoro, chloro, bromo or iodo.

“Heteroalkyl” means alkyl, as defined in this Application, provided thatone or more of the atoms within the alkyl chain is a heteroatom. Inparticular embodiments, “heteroalkyl,” either alone or represented alongwith another radical, can be a hetero(C₁₋₂₀)alkyl, a hetero(C₁₋₁₅)alkyl,a hetero(C₁₋₁₀)alkyl, a hetero(C₁₋₅)alkyl, a hetero(C₁₋₃)alkyl or ahetero(C₁₋₂)alkyl. Alternatively, “heteroalkyl,” either alone orrepresented along with another radical, can be a hetero(C₁)alkyl, ahetero(C₂)alkyl or a hetero(C₃)alkyl.

“Heteroaryl” means a monocyclic, bicyclic or polycyclic aromatic groupwherein at least one ring atom is a heteroatom and the remaining ringatoms are carbon. Monocyclic heteroaryl groups include, but are notlimited to, cyclic aromatic groups having five or six ring atoms,wherein at least one ring atom is a heteroatom and the remaining ringatoms are carbon. The nitrogen atoms can be optionally quaternerized andthe sulfur atoms can be optionally oxidized. Heteroaryl groups of thisinvention include, but are not limited to, those derived from furan,imidazole, isothiazole, isoxazole, oxadiazole, oxazole,1,2,3-oxadiazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,pyrroline, thiazole, 1,3,4-thiadiazole, triazole and tetrazole.“Heteroaryl” also includes, but is not limited to, bicyclic or tricyclicrings, wherein the heteroaryl ring is fused to one or two ringsindependently selected from the group consisting of an aryl ring, acycloalkyl ring, a cycloalkenyl ring, and another monocyclic heteroarylor heterocycloalkyl ring. These bicyclic or tricyclic heteroarylsinclude, but are not limited to, those derived from benzo[b]furan,benzo[b]thiophene, benzimidazole, imidazo[4,5-c]pyridine, quinazoline,thieno[2,3-c]pyridine, thieno[3,2-b]pyridine, thieno[2,3-b]pyridine,indolizine, imidazo[1,2a]pyridine, quinoline, isoquinoline, phthalazine,quinoxaline, naphthyridine, quinolizine, indole, isoindole, indazole,indoline, benzoxazole, benzopyrazole, benzothiazole,imidazo[1,5-a]pyridine, pyrazolo[1,5-a]pyridine,imidazo[1,2-a]pyrimidine, imidazo[1,2-c]pyrimidine,imidazo[1,5-a]pyrimidine, imidazo[1,5-c]pyrimidine,pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridine,pyrrolo[3,2-b]pyridine, pyrrolo[2,3-d]pyrimidine,pyrrolo[3,2-d]pyrimidine, pyrrolo[2,3-b]pyrazine,pyrazolo[1,5-a]pyridine, pyrrolo[1,2-b]pyridazine,pyrrolo[1,2-c]pyrimidine, pyrrolo[1,2-a]pyrimidine,pyrrolo[1,2-a]pyrazine, triazo[1,5-a]pyridine, pteridine, purine,carbazole, acridine, phenazine, phenothiazene, phenoxazine,1,2-dihydropyrrolo[3,2,1-hi]indole, indolizine, pyrido[1,2-a]indole and2(1H)-pyridinone. The bicyclic or tricyclic heteroaryl rings can beattached to the parent molecule through either the heteroaryl groupitself or the aryl, cycloalkyl, cycloalkenyl or heterocycloalkyl groupto which it is fused. The heteroaryl groups of this invention can besubstituted or unsubstituted. In particular embodiments, “heteroaryl,”either alone or represented along with another radical, can be ahetero(C₁₋₁₃)aryl, a hetero(C₂₋₁₃)aryl, a hetero(C₂₋₆)aryl, ahetero(C₃₋₉)aryl or a hetero(C₅₋₉)aryl. Alternatively, “heteroaryl,”either alone or represented along with another radical, can be ahetero(C₃)aryl, a hetero(C₄)aryl, a hetero(C₅)aryl, a hetero(C₆)aryl, ahetero(C₇)aryl, a hetero(C₈)aryl or a hetero(C₉)aryl.

“Heteroatom” refers to an atom that is not a carbon atom. Particularexamples of heteroatoms include, but are not limited to, nitrogen,oxygen, and sulfur.

“Heteroatom moiety” includes a moiety where the atom by which the moietyis attached is not a carbon. Examples of heteroatom moieties include—NR—, —N³⁰ (O⁻)═, —O—, —S— or —S(O)₂—, wherein R is hydrogen or afurther substituent.

“Heterobicycloalkyl” means bicycloalkyl, as defined in this Application,provided that one or more of the atoms within the ring is a heteroatom.For example hetero(C₉₋₁₂)bicycloalkyl as used in this applicationincludes, but is not limited to, 3-aza-bicyclo[4.1.0]hept-3-yl,2-aza-bicyclo[3.1.0]hex-2-yl, 3-aza-bicyclo[3.1.0]hex-3-yl, and thelike. In particular embodiments, “heterobicycloalkyl,” either alone orrepresented along with another radical, can be ahetero(C₁₋₁₄)bicycloalkyl, a hetero(C₄₋₁₄)bicycloalkyl, ahetero(C₄₋₉)bicycloalkyl or a hetero(C₅₋₉)bicycloalkyl. Alternatively,“heterobicycloalkyl,” either alone or represented along with anotherradical, can be a hetero(C₅)bicycloalkyl, hetero(C₆)bicycloalkyl,hetero(C₇)bicycloalkyl, hetero(C₈)bicycloalkyl or ahetero(C₉)bicycloalkyl.

“Heterobicycloaryl” means bicycloaryl, as defined in this Application,provided that one or more of the atoms within the ring is a heteroatom.For example, hetero(C₄₋₁₂)bicycloaryl as used in this Applicationincludes, but is not limited to, 2-amino-4-oxo-3,4-dihydropteridin-6-yl,tetrahydroisoquinolinyl, and the like. In particular embodiments,“heterobicycloaryl,” either alone or represented along with anotherradical, can be a hetero(C₁₋₁₄)bicycloaryl, a hetero(C₄₋₁₄)bicycloaryl,a hetero(C₄₋₉)bicycloarylor a hetero(C₅₋₉)bicycloaryl. Alternatively,“heterobicycloaryl,” either alone or represented along with anotherradical, can be a hetero(C₅)bicycloaryl, hetero(C₆)bicycloaryl,hetero(C₇)bicycloaryl, hetero(C₈)bicycloaryl or a hetero(C₉)bicycloaryl.

“Heterocycloalkyl” means cycloalkyl, as defined in this Application,provided that one or more of the atoms forming the ring is a heteroatomselected, independently from N, O, or S, Non-exclusive examples ofheterocycloalkyl include piperidyl, 4-morpholyl, 4-piperazinyl,pyrrolidinyl, perhydropyrrolizinyl, 1,4-diazaperhydroepinyl,1,3-dioxanyl, 1,4-dioxanyl and the like. In particular embodiments,“heterocycloalkyl,” either alone or represented along with anotherradical, can be a hetero(C₁₋₁₃)cycloalkyl, a hetero(C₁₋₉)cycloalkyl, ahetero(C₁₋₆)cycloalkyl, a hetero(C₅₋₉)cycloalkyl or ahetero(C₂₋₆)cycloalkyl. Alternatively, “heterocycloalkyl,” either aloneor represented along with another radical, can be ahetero(C₂)cycloalkyl, a hetero(C₃)cycloalkyl, a hetero(C₄)cycloalkyl, ahetero(C₅)cycloalkyl, a hetero(C₆)cycloalkyl, hetero(C₇)cycloalkyl,hetero(C₈)cycloalkyl or a hetero(C₉)cycloalkyl.

“Heterocycloalkylene” means cycloalkylene, as defined in thisApplication, provided that one or more of the ring member carbon atomsis replaced by a heteroatom. In particular embodiments,“heterocycloalkylene,” either alone or represented along with anotherradical, can be a hetero(C₁₋₁₃)cycloalkylene, ahetero(C₁₋₉)cycloalkylene, a hetero(C₁₋₆)cycloalkylene, ahetero(C₅₋₉)cycloalkylene or a hetero(C₂₋₆)cycloalkylene. Alternatively,“heterocycloalkylene,” either alone or represented along with anotherradical, can be a hetero(C₂)cycloalkylene, a hetero(C₃)cycloalkylene, ahetero(C₄)cycloalkylene, a hetero(C₅)cycloalkylene, ahetero(C₆)cycloalkylene, hetero(C₇)cycloalkylene,hetero(C₈)cycloalkylene or a hetero(C₉)cycloalkylene.

“Hydroxy” means the radical —OH.

“IC₅₀” means the molar concentration of an inhibitor that produces 50%inhibition of the target enzyme.

“Imino” means the radical —CR(═NR′) and/or —C(═NR′)—, wherein R and R′are each independently hydrogen or a further substituent.

“Isomers” means compounds having identical molecular formulae butdiffering in the nature or sequence of bonding of their atoms or in thearrangement of their atoms in space. Isomers that differ in thearrangement of their atoms in space are termed “stereoisomers.”Stereoisomers that are not mirror images of one another are termed“diastereomers” and stereoisomers that are nonsuperimposable mirrorimages are termed “enantiomers” or sometimes “optical isomers.” A carbonatom bonded to four nonidentical substituents is termed a “chiralcenter.” A compound with one chiral center has two enantiomeric forms ofopposite chirality. A mixture of the two enantiomeric forms is termed a“racemic mixture.” A compound that has more than one chiral center has2^(n-1) enantiomeric pairs, where n is the number of chiral centers.Compounds with more than one chiral center may exist as ether anindividual diastereomer or as a mixture of diastereomers, termed a“diastereomeric mixture.” When one chiral center is present astereoisomer may be characterized by the absolute configuration of thatchiral center. Absolute configuration refers to the arrangement in spaceof the substituents attached to the chiral center. Enantiomers arecharacterized by the absolute configuration of their chiral centers anddescribed by the R- and S-sequencing rules of Cahn, Ingold and Prelog.Conventions for stereochemical nomenclature, methods for thedetermination of stereochemistry and the separation of stereoisomers arewell known in the art (e.g., see “Advanced Organic Chemistry”, 4thedition, March, Jerry, John Wiley & Sons, New York, 1992).

“Leaving group” means the group with the meaning conventionallyassociated with it in synthetic organic chemistry, i.e., an atom orgroup displaceable under reaction (e.g., alkylating) conditions.Examples of leaving groups include, but are not limited to, halo (e.g.,F, Cl, Br and I), alkyl (e.g., methyl and ethyl) and sulfonyloxy (e.g.,mesyloxy, ethanesulfonyloxy, benzenesulfonyloxy and tosyloxy),thiomethyl, thienyloxy, dihalophosphinoyloxy, tetrahalophosphoxy,benzyloxy, isopropyloxy, acyloxy, and the like.

“Moiety providing X atom separation” and “linker providing X atomseparation” between two other moieties mean that the chain of atomsdirectly linking the two other moieties is X atoms in length. When X isgiven as a range (e.g., X₁-X₂), then the chain of atoms is at least X₁and not more than X₂ atoms in length. It is understood that the chain ofatoms can be formed from a combination of atoms including, for example,carbon, nitrogen, sulfur and oxygen atoms. Further, each atom canoptionally be bound to one or more substituents, as valencies allow. Inaddition, the chain of atoms can form part of a ring. Accordingly, inone embodiment, a moiety providing X atom separation between two othermoieties (R and R′) can be represented by R-(L)_(X)-R′ where each L isindependently selected from the group consisting of CR″R′″, NR″″, O, S,CO, CS, C═NR′″″, SO, SO₂, and the like, where any two or more of R″,R′″, R″″ and R′″″ can be taken together to form a substituted orunsubstituted ring.

“Nitro” means the radical —NO₂.

“Oxaalkyl” means an alkyl, as defined above, except where one or more ofthe carbon atoms forming the alkyl chain are replaced with oxygen atoms(—O— or —OR, wherein R is hydrogen or a further substituent). Forexample, an oxa(C₁₋₁₀)alkyl refers to a chain comprising between 1 and10 carbons and one or more oxygen atoms.

“Oxoalkyl” means an alkyl, as defined above, except where one or more ofthe carbon atoms forming the alkyl chain are replaced with carbonylgroups (—C(═O)— or —C(═O)—R, wherein R is hydrogen or a furthersubstituent). The carbonyl group may be an aldehyde, ketone, ester,amide, acid or acid halide. For example, an oxo(C₁₋₁₀)alkyl refers to achain comprising between 1 and 10 carbon atoms and one or more carbonylgroups.

“Oxy” means the radical —O— or —OR, wherein R is hydrogen or a furthersubstituent. Accordingly, it is noted that the oxy radical may befurther substituted with a variety of substituents to form different oxygroups including hydroxy, alkoxy, aryloxy, heteroaryloxy or carbonyloxy.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic and neitherbiologically nor otherwise undesirable and includes that which isacceptable for veterinary use as well as human pharmaceutical use.

“Pharmaceutically acceptable salts” means salts of compounds of thepresent invention which are pharmaceutically acceptable, as definedabove, and which possess the desired pharmacological activity. Suchsalts include acid addition salts formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or with organic acids such as aceticacid, propionic acid, hexanoic acid, heptanoic acid,cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid,malonic acid, succinic acid, malic acid, maleic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, o-(4-hydroxybenzoyl)benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, p-chlorobenzenesulfonic acid,2-naphthalenesulfonic acid, p-toluenesulfonic acid, camphorsulfonicacid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonicacid, 4,4′-methylenebis(3-hydroxy-2-ene-1-carboxylic acid),3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid and the like.

Pharmaceutically acceptable salts also include base addition salts whichmay be formed when acidic protons present are capable of reacting withinorganic or organic bases. Acceptable inorganic bases include sodiumhydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide andcalcium hydroxide. Acceptable organic bases include ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine and thelike.

“Polycyclic ring” includes bicyclic and multi-cyclic rings. Theindividual rings comprising the polycyclic ring can be fused, spiro orbridging rings.

“Prodrug” means a compound that is convertible in vivo metabolicallyinto an inhibitor according to the present invention. The prodrug itselfmay or may not also have activity with respect to a given targetprotein. For example, a compound comprising a hydroxy group may beadministered as an ester that is converted by hydrolysis in vivo to thehydroxy compound. Suitable esters that may be converted in vivo intohydroxy compounds include acetates, citrates, lactates, phosphates,tartrates, malonates, oxalates, salicylates, propionates, succinates,fumarates, maleates, methylene-bis-b-hydroxynaphthoates, gentisates,isethionates, di-p-toluoyltartrates, methanesulfonates,ethanesulfonates, benzenesulfonates, p-toluenesulfonates,cyclohexylsulfamates, quinates, esters of amino acids, and the like.Similarly, a compound comprising an amine group may be administered asan amide that is converted by hydrolysis in vivo to the amine compound.

“Protected derivatives” means derivatives of inhibitors in which areactive site or sites are blocked with protecting groups. Protectedderivatives are useful in the preparation of inhibitors or in themselvesmay be active as inhibitors. A comprehensive list of suitable protectinggroups can be found in T. W. Greene, Protecting Groups in OrganicSynthesis, 3rd edition, John Wiley & Sons, Inc. 1999.

“Ring” and “ring assembly” means a carbocyclic or a heterocyclic systemand includes aromatic and non-aromatic systems. The system can bemonocyclic, bicyclic or polycyclic. In addition, for bicyclic andpolycyclic systems, the individual rings comprising the polycyclic ringcan be fused, spiro or bridging rings.

“Subject” and “patient” includes humans, non-human mammals (e.g., dogs,cats, rabbits, cattle, horses, sheep, goats, swine, deer, and the like)and non-mammals (e.g., birds, and the like).

“Substituent convertible to hydrogen in vivo” means any group that isconvertible to a hydrogen atom by enzymological or chemical meansincluding, but not limited to, hydrolysis and hydrogenolysis. Examplesinclude hydrolyzable groups, such as acyl groups, groups having anoxycarbonyl group, amino acid residues, peptide residues,o-nitrophenylsulfenyl, trimethylsilyl, tetrahydro-pyranyl,diphenylphosphinyl, and the like. Examples of acyl groups includeformyl, acetyl, trifluoroacetyl, and the like. Examples of groups havingan oxycarbonyl group include ethoxycarbonyl, t-butoxycarbonyl[(CH₃)₃C—OCO—], benzyloxycarbonyl, p-methoxybenzyloxycarbonyl,vinyloxycarbonyl, β-(p-toluenesulfonyl)ethoxycarbonyl, and the like.Examples of suitable amino acid residues include amino acid residues perse and amino acid residues that are protected with a protecting group.Suitable amino acid residues include, but are not limited to, residuesof Gly (glycine), Ala (alanine; CH₃CH(NH₂)CO—), Arg (arginine), Asn(asparagine), Asp (aspartic acid), Cys (cysteine), Glu (glutamic acid),His (histidine), Ile (isoleucine), Leu (leucine; (CH₃)₂CHCH₂CH(NH₂)CO—),Lys (lysine), Met (methionine), Phe (phenylalanine), Pro (proline), Ser(serine), Thr (threonine), Trp (tryptophan), Tyr (tyrosine), Val(valine), Nva (norvaline), Hse (homoserine), 4-Hyp (4-hydroxyproline),5-Hyl (5-hydroxylysine), Orn (ornithine) and β-Ala. Examples of suitableprotecting groups include those typically employed in peptide synthesis,including acyl groups (such as formyl and acetyl), arylmethyloxycarbonylgroups (such as benzyloxycarbonyl and p-nitrobenzyloxycarbonyl),t-butoxycarbonyl groups [(CH₃)₃C—OCO—], and the like. Suitable peptideresidues include peptide residues comprising two to five, and optionallytwo to three, of the aforesaid amino acid residues. Examples of suchpeptide residues include, but are not limited to, residues of suchpeptides as Ala-Ala [CH₃CH(NH₂)CO—NHCH(CH₃)CO—], Gly-Phe, Nva-Nva,Ala-Phe, Gly-Gly, Gly-Gly-Gly, Ala-Met, Met-Met, Leu-Met and Ala-Leu.The residues of these amino acids or peptides can be present instereochemical configurations of the D-form, the L-form or mixturesthereof. In addition, the amino acid or peptide residue may have anasymmetric carbon atom. Examples of suitable amino acid residues havingan asymmetric carbon atom include residues of Ala, Leu, Phe, Trp, Nva,Val, Met, Ser, Lys, Thr and Tyr. Peptide residues having an asymmetriccarbon atom include peptide residues having one or more constituentamino acid residues having an asymmetric carbon atom. Examples ofsuitable amino acid protecting groups include those typically employedin peptide synthesis, including acyl groups (such as formyl and acetyl),arylmethyloxycarbonyl groups (such as benzyloxycarbonyl andp-nitrobenzyloxycarbonyl), t-butoxycarbonyl groups [(CH₃)₃C—OCO—], andthe like. Other examples of substituents “convertible to hydrogen invivo” include reductively eliminable hydrogenolyzable groups. Examplesof suitable reductively eliminable hydrogenolyzable groups include, butare not limited to, arylsulfonyl groups (such as o-toluenesulfonyl);methyl groups substituted with phenyl or benzyloxy (such as benzyl,trityl and benzyloxymethyl); arylmethoxycarbonyl groups (such asbenzyloxycarbonyl and o-methoxy-benzyloxycarbonyl); andhalogenoethoxycarbonyl groups (such as β,β,β-trichloroethoxycarbonyl andβ-iodoethoxycarbonyl).

“Substituted or unsubstituted” means that a given moiety may consist ofonly hydrogen substituents through available valencies (unsubstituted)or may further comprise one or more non-hydrogen substituents throughavailable valencies (substituted) that are not otherwise specified bythe name of the given moiety. For example, isopropyl is an example of anethylene moiety that is substituted by —CH₃. In general, a non-hydrogensubstituent may be any substituent that may be bound to an atom of thegiven moiety that is specified to be substituted. Examples ofsubstituents include, but are not limited to, aldehyde, alicyclic,aliphatic, (C₁₋₁₀)alkyl, alkylene, alkylidene, amide, amino, aminoalkyl,aromatic, aryl, bicycloalkyl, bicycloaryl, carbamoyl, carbocyclyl,carboxyl, carbonyl group, cycloalkyl, cycloalkylene, ester, halo,heterobicycloalkyl, heterocycloalkylene, heteroaryl, heterobicycloaryl,heterocycloalkyl, oxo, hydroxy, iminoketone, ketone, nitro, oxaalkyl,and oxoalkyl moieties, each of which may optionally also be substitutedor unsubstituted. In one particular embodiment, examples of substituentsinclude, but are not limited to, hydrogen, halo, nitro, cyano, thio,oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino,(C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl,(C₁₋₁₀)azaalkyl, imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl. In addition, the substituent is itselfoptionally substituted by a further substituent. In one particularembodiment, examples of the further substituent include, but are notlimited to, hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy,carbonyl, oxycarbonyl, aminocarbonyl, amino, (C₁₋₁₀)alkylamino,sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl, hetero(C₃₋₁₂)bicycloalkyl,(C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl andhetero(C₄₋₁₂)bicycloaryl.

“Sulfinyl” means the radical —SO— and/or —SO—R, wherein R is hydrogen ora further substituent. It is noted that the sulfinyl radical may befurther substituted with a variety of substituents to form differentsulfinyl groups including sulfinic acids, sulfinamides, sulfinyl esters,and sulfoxides.

“Sulfonyl” means the radical —SO₂— and/or —SO₂—R, wherein R is hydrogenor a further substituent. It is noted that the sulfonyl radical may befurther substituted with a variety of substituents to form differentsulfonyl groups including sulfonic acids, sulfonamides, sulfonateesters, and sulfones.

“Therapeutically effective amount” means that amount which, whenadministered to an animal for treating a disease, is sufficient toeffect such treatment for the disease.

“Thio” denotes replacement of an oxygen by a sulfur and includes, but isnot limited to, —SR, —S— and ═S containing groups.

“Thioalkyl” means an alkyl, as defined above, except where one or moreof the carbon atoms forming the alkyl chain are replaced with sulfuratoms (—S— or —S—R, wherein R is hydrogen or a further substituent). Forexample, a thio(C₁₋₁₀)alkyl refers to a chain comprising between 1 and10 carbons and one or more sulfur atoms.

“Thiocarbonyl” means the radical —C(═S)— and/or —C(═S)—R, wherein R ishydrogen or a further substituent. It is noted that the thiocarbonylradical may be further substituted with a variety of substituents toform different thiocarbonyl groups including thioacids, thioamides,thioesters, and thioketones.

“Treatment” or “treating” means any administration of a compound of thepresent invention and includes:

(1) preventing the disease from occurring in an animal which may bepredisposed to the disease but does not yet experience or display thepathology or symptomatology of the disease,

(2) inhibiting the disease in an animal that is experiencing ordisplaying the pathology or symptomatology of the diseased (i.e.,arresting further development of the pathology and/or symptomatology),or

(3) ameliorating the disease in an animal that is experiencing ordisplaying the pathology or symptomatology of the diseased (i.e.,reversing the pathology and/or symptomatology).

It is noted in regard to all of the definitions provided herein that thedefinitions should be interpreted as being open ended in the sense thatfurther substituents beyond those specified may be included. Hence, a C₁alkyl indicates that there is one carbon atom but does not indicate whatare the substituents on the carbon atom. Hence, a (C₁)alkyl comprisesmethyl (i.e., —CH₃) as well as —CRR′R″ where R, R′, and R″ may eachindependently be hydrogen or a further substituent where the atomattached to the carbon is a heteroatom or cyano. Hence, CF₃, CH₂OH andCH₂CN, for example, are all (C₁)alkyls. Similarly, terms such asalkylamino and the like comprise dialkylamino and the like.

A compound having a formula that is represented with a dashed bond isintended to include the formulae optionally having zero, one or moredouble bonds, as exemplified and shown below:

-   -   represents

etc.

In addition, atoms making up the compounds of the present invention areintended to include all isotopic forms of such atoms. Isotopes, as usedherein, include those atoms having the same atomic number but differentmass numbers. By way of general example and without limitation, isotopesof hydrogen include tritium and deuterium, and isotopes of carboninclude ¹³C and ¹⁴C.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds that may be used to inhibitMitogen-Activated Protein Kinases (referred to herein as MEK) and, inparticular, MAPK/ERK Kinase 1 (referred to herein as MEK1) and/orMAPK/ERK Kinase 2 (referred to herein as MEK2). The present inventionalso relates to pharmaceutical compositions, kits and articles ofmanufacture comprising such compounds. In addition, the presentinvention relates to methods and intermediates useful for making thecompounds. Further, the present invention relates to methods of usingsaid compounds. It is noted that the compounds of the present inventionmay also possess activity for other members of the same protein familyand thus may be used to address disease states associated with theseother family members.

MEK belongs to the protein kinase family of enzymes. Themitogen-activated protein kinase (MAPK) pathways are evolutionarilyconserved from yeast to man and respond to a variety of extracellularsignals to induce cell differentiation and proliferation. Theextracellular-regulated kinase (ERK) cascade is one of three major MAPKsignaling pathways and is the predominant cascade that controls cellproliferation, migration, division, and differentiation (Schaeffer, H.J., and Weber, M. J. (1999) Mol. Cell. Biol. 19, 2435-2444). In thispathway, binding of GTP to the Ras protein initiates a three proteinkinase cascade, which leads to ERK activation through the interveningprotein kinases Raf-1 and MEK1/2. The MEK1/2 kinases aredual-specificity threonine/tyrosine kinases that activate the downstreamERK kinase by phosphorylating specific ERK threonine and tyrosineresidues, and are themselves activated by phosphorylation of MEK serineresidues by the upstream RAF kinase. MEK1 and MEK2 share a high degreeof amino acid sequence similarity, particularly in their kinase domains,and both are capable of phosphorylating ERK (Zheng, C-F., and Guan, K.(1993) J. Biol. Chem. 268, 11435-11439).

Multiple studies have linked the RAF/MEK/ERK signaling pathway to thegrowth and survival of many diverse human tumors including, but notlimited to cancers of the colon, pancreas ovaries, and non-small-celllung cancers (reviewed in: Sebolt-Leopold, J. S, and Herrera R. (2004)Nature Reviews: Cancer, 4, 937-947). For these reasons there has beenconsiderable interest in developing small molecule pharmaceuticalinhibitors of this pathway.

It is noted that the compounds of the present invention may also possessinhibitory activity for other protein kinase family members and thus maybe used to address disease states associated with these other familymembers.

Crystal Structure of MEK2

Takeda San Diego, Inc. solved the crystal structure of MEK2. Knowledgeof the crystal structure was used to guide the design of the inhibitorsprovided herein.

The overall architecture of the MEK proteins resembles the conserved,two domain protein kinase fold, consisting of a large C-terminalcomprised mostly of an α-helical domain and a smaller N-terminal lobecomprised primarily of a β-sheet. The N-lobe typically contains a singleα-helix termed the Control or C-helix which influences the productivebinding of nucleotides at the active region, which is located at thecleft between the two domains. Additionally, productive binding ofnucleotide and substrates can be dependent upon an Activation Loop, orA-Loop, which is in an extended conformation when active, but often in afolded-back inactive conformation that at least partially occludes theactive region. Phosphorylation of specific residues within the A-Loopcan help stabilize the active, extended conformation. Common kinaseinhibitory mechanisms typically target structural alterations within theC-Helix or A Loop.

MEK1 and/or MEK2 Inhibitors and Processes for Making Thereof

In one of its aspects, the present invention relates to compounds thatare useful as MEK inhibitors. In one embodiment, MEK inhibitors of thepresent invention comprise:

or a polymorph, solvate, ester, tautomer, enantiomer, pharmaceuticallyacceptable salt or prodrug thereof, wherein

-   -   X₁ and X₂ are each independently selected from the group        consisting of CR₆R₇, CO, CS and NR₈;    -   X₃ and X₄ are each independently selected from the group        consisting of CR₇ and N;    -   X₅ is selected from the group consisting of CR₆R₇, CS and NR₈;    -   R₁ is selected from the group consisting of (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂ is hydrogen or a substituent convertible in vivo to hydrogen;    -   R₃ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, alkoxy, hydroxyalkoxy, aryloxy,        heteroaryloxy, carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, amino(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, provided that R₃ is absent when        the atom to which it is bound forms part of a double bond;    -   R₄ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, amido, (C₁₋₁₀)alkylamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, amido(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, provided that R₄ is absent when        the atom to which it is bound forms part of a double bond;    -   R₅ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy, carbonyl,        oxycarbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₅ and R₄ are taken together to        form a substituted or unsubstituted ring, provided that R₅ is        absent when the atom to which it is bound forms part of a double        bond;    -   R₆ and R₇ are each independently selected from the group        consisting of hydrogen, halo, cyano, heteroaryloxy, carbonyl,        oxycarbonyl, aminocarbonyl, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₇ and R₅ are taken together to        form a substituted or unsubstituted ring, provided that R₇ is        absent when the atom to which it is bound forms part of a double        bond; and    -   R₈ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, provided that R₈ is absent when        the atom to which it is bound forms part of a double bond.

In another embodiment, MEK inhibitors of the present invention comprise:

In still another embodiment, MEK inhibitors of the present inventioncomprise:

In yet another embodiment, MEK inhibitors of the present inventioncomprise:

-   -   wherein    -   R₉ is selected from the group consisting of hydrogen,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In a further embodiment, MEK inhibitors of the present inventioncomprise:

-   -   wherein    -   L is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between the atoms to which L is attached, wherein the        atoms of the linker providing the separation are selected from        the group consisting of carbon, oxygen, nitrogen, and sulfur;        and    -   R₁₀ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In still a further embodiment, MEK inhibitors of the present inventioncomprise:

-   -   wherein    -   L is absent or a linker providing 1, 2, 3, 4, 5 or 6 atom        separation between the atoms to which L is attached, wherein the        atoms of the linker providing the separation are selected from        the group consisting of carbon, oxygen, nitrogen, and sulfur;        and    -   R₁₁ is selected from the group consisting of hydrogen,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl, hetero        (C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In yet a further embodiment, MEK inhibitors of the present inventioncomprise:

-   -   wherein    -   n is selected from the group consisting of 1, 2, 3, 4, 5 and 6;    -   R₁₁ is selected from the group consisting of hydrogen,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   each R₁₂ and R₁₃ is independently selected from the group        consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,        carbonyloxy, alkoxy, aryloxy, heteroaryloxy, carbonyl,        oxycarbonyl, aminocarbonyl, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In another embodiment, MEK inhibitors of the present invention comprise:

-   -   wherein    -   m is selected from the group consisting of 0, 1, 2, 3, 4 and 5;        and    -   each R₁₄ is independently selected from the group consisting of        hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,        alkoxy, aryloxy, heteroaryloxy, carbonyl, oxycarbonyl,        aminocarbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or two R₁₄ are taken together to        form a substituted or unsubstituted ring.

In still another embodiment, MEK inhibitors of the present inventioncomprise:

-   -   wherein    -   R_(14a) and R_(14c) are each independently selected from the        group consisting of hydrogen, halo, nitro, cyano, thio, oxy,        hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy, carbonyl,        oxycarbonyl, aminocarbonyl, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In yet another embodiment, MEK inhibitors of the present inventioncomprise:

-   -   wherein    -   m is selected from the group consisting of 0, 1, 2, 3, 4 and 5;    -   n is selected from the group consisting of 1, 2, 3, 4, 5 and 6;    -   R₁₁ is selected from the group consisting of hydrogen,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   each R₁₂ and R₁₃ is independently selected from the group        consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,        carbonyloxy, alkoxy, aryloxy, heteroaryloxy, carbonyl,        oxycarbonyl, aminocarbonyl, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   each R₁₄ is independently selected from the group consisting of        hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,        alkoxy, aryloxy, heteroaryloxy, carbonyl, oxycarbonyl,        aminocarbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or two R₁₄ are taken together to        form a substituted or unsubstituted ring.

In a further embodiment, MEK inhibitors of the present inventioncomprise:

-   -   wherein    -   p is selected from the group consisting of 1, 2, 3, 4 and 5;    -   each R₁₅ and R₁₆ are independently selected from the group        consisting of hydrogen, halo, nitro, cyano, thio, oxy, hydroxy,        carbonyloxy, alkoxy, aryloxy, heteroaryloxy, carbonyl,        oxycarbonyl, aminocarbonyl, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   R₁₇ is selected from the group consisting of hydrogen, halo,        nitro, cyano, thio, oxy, hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy,        (C₄₋₁₂)aryloxy, hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl,        aminocarbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl, (C₁₋₁₀)oxaalkyl,        (C₁₋₁₀)oxoalkyl, imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cyclo        alkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl,        aryl(C₁₋₁₀)alkyl, hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl,        (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted.

In another of its aspects, the present invention relates to methods ofmaking compounds that are useful as MEK inhibitors. In one embodiment,the methods comprise the steps of:

treating a compound comprising the formula

under conditions that form a first reaction product comprising theformula

reacting the first reaction product with a compound comprising theformula

under conditions that form a second reaction product comprising theformula

treating the second reaction product under conditions that form a thirdreaction product comprising the formula

and

reacting the third reaction product with a compound comprising theformula

under conditions that form a product comprising the formula

-   -   wherein    -   X is halo;    -   X₁ and X₂ are each independently selected from the group        consisting of CR₆R₇, CO, CS and NR₈;    -   X₅ is selected from the group consisting of CR₆R₇, CO, CS and        NR₈;    -   each R_(a) is independently a substituted or unsubstituted        (C₁₋₃₋)alkyl;    -   R_(b), together with the O to which it is bound, is a leaving        group;    -   R₁ is selected from the group consisting of (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂ is hydrogen or a substituent convertible in vivo to hydrogen;    -   R₃ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, alkoxy, hydroxyalkoxy, aryloxy,        heteroaryloxy, carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, amino(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, provided that R₃ is absent when        the atom to which it is bound forms part of a double bond;    -   R₄ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, amido, (C₁₋₁₀)alkylamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, amido(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, provided that R₄ is absent when        the atom to which it is bound forms part of a double bond;    -   R₅ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy, carbonyl,        oxycarbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₅ and R₄ are taken together to        form a substituted or unsubstituted ring, provided that R₅ is        absent when the atom to which it is bound forms part of a double        bond;    -   R₆ and R₇ are each independently selected from the group        consisting of hydrogen, halo, cyano, heteroaryloxy, carbonyl,        oxycarbonyl, aminocarbonyl, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₇ and R₅ are taken together to        form a substituted or unsubstituted ring, provided that R₇ is        absent when the atom to which it is bound forms part of a double        bond; and    -   R₈ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, provided that R₈ is absent when        the atom to which it is bound forms part of a double bond.

In another embodiment, the methods comprise the steps of:

reacting a compound comprising the formula

with a compound comprising the formula

under conditions that form a first reaction product comprising theformula

treating the first reaction product under conditions that form a secondreaction product comprising the formula

and

reacting the second reaction product with a compound comprising theformula

under conditions that form a product comprising the formula

-   -   wherein    -   m is selected from the group consisting of 0, 1, 2, 3, 4 and 5;    -   X₁ and X₂ are each independently selected from the group        consisting of CR₆R₇, CO, CS and NR₈;    -   X₅ is selected from the group consisting of CR₆R₇, CO, CS and        NR₈;    -   each R_(a) is independently a substituted or unsubstituted        (C₁₋₃₋)alkyl;    -   R_(b), together with the O to which it is bound, is a leaving        group;    -   R₂ is hydrogen or a substituent convertible in vivo to hydrogen;    -   R₃ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, alkoxy, hydroxyalkoxy, aryloxy,        heteroaryloxy, carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo (C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, amino (C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, provided that R₃ is absent when        the atom to which it is bound forms part of a double bond;    -   R₄ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, amido, (C₁₋₁₀)alkylamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, amido(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, provided that R₄ is absent when        the atom to which it is bound forms part of a double bond;    -   R₅ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy, carbonyl,        oxycarbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicyclo aryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₅ and R₄ are taken together to        form a substituted or unsubstituted ring, provided that R₅ is        absent when the atom to which it is bound forms part of a double        bond;    -   R₆ and R₇ are each independently selected from the group        consisting of hydrogen, halo, cyano, heteroaryloxy, carbonyl,        oxycarbonyl, aminocarbonyl, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₇ and R₅ are taken together to        form a substituted or unsubstituted ring, provided that R₇ is        absent when the atom to which it is bound forms part of a double        bond;    -   R₈ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, provided that R₈ is absent when        the atom to which it is bound forms part of a double bond; and    -   each R₁₄ is independently selected from the group consisting of        hydrogen, halo, nitro, cyano, thio, oxy, hydroxy, carbonyloxy,        alkoxy, aryloxy, heteroaryloxy, carbonyl, oxycarbonyl,        aminocarbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or two R₁₄ are taken together to        form a substituted or unsubstituted ring.

In still another embodiment, the methods comprise the steps of:

reacting a compound comprising the formula

under conditions that form a first reaction product comprising theformula

reacting the first reaction product with a compound comprising theformula

under conditions that form a second reaction product comprising theformula

reacting the second reaction product with 4-methylbenzene-1-sulfonylchloride under conditions that form a third reaction product comprisingthe formula

and

reacting the third reaction product with a compound comprising theformula

under conditions that form a product comprising the formula

-   -   wherein    -   each R_(a) is independently a substituted or unsubstituted        (C₁₋₃₋)alkyl;    -   R_(b), together with the O to which it is bound, is a leaving        group;    -   R₁ is selected from the group consisting of (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂ is hydrogen or a substituent convertible in vivo to hydrogen;    -   R₃ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, alkoxy, hydroxyalkoxy, aryloxy,        heteroaryloxy, carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, amino(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, provided that R₃ is absent when        the atom to which it is bound forms part of a double bond;    -   R₅ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy, carbonyl,        oxycarbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicyclo aryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₅ and R₄ are taken together to        form a substituted or unsubstituted ring, provided that R₅ is        absent when the atom to which it is bound forms part of a double        bond.

In a further embodiment, the methods comprise the steps of:

reacting a compound having the formula

with a compound having the formula

under conditions that form a first reaction product having the formula

treating the first reaction product under conditions that form a secondreaction product having the formula

and

reacting the second reaction product with a compound having the formula

under conditions that form a third reaction product having the formula

-   -   wherein    -   each R_(a) is independently a substituted or unsubstituted        (C₁₋₃₋)alkyl;    -   R₁ is selected from the group consisting of (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted;    -   R₂ is hydrogen or a substituent convertible in vivo to hydrogen;    -   R₃ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, alkoxy, hydroxyalkoxy, aryloxy,        heteroaryloxy, carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, amino(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, provided that R₃ is absent when        the atom to which it is bound forms part of a double bond;    -   R₅ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy, carbonyl,        oxycarbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, provided that R₅ is absent when        the atom to which it is bound forms part of a double bond;    -   R₆ is selected from the group consisting of hydrogen, halo,        cyano, heteroaryloxy, carbonyl, oxycarbonyl, aminocarbonyl,        amino, (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl,        sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted; and    -   X is halo.

In still another of its aspects, the present invention relates tointermediates that are useful in making MEK inhibitors. In oneembodiment, the intermediates comprise

-   -   wherein    -   X₁ and X₂ are each independently selected from the group        consisting of CR₆R₇, CO, CS and NR₈;    -   X₃ and X₄ are each independently selected from the group        consisting of CR₇ and N;    -   X₅ is selected from the group consisting of CR₆R₇, CS and NR₈;    -   R₃ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, alkoxy, hydroxyalkoxy, aryloxy,        heteroaryloxy, carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, amino(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, provided that R₃ is absent when        the atom to which it is bound forms part of a double bond;    -   R₄ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, amido, (C₁₋₁₀)alkylamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, amido(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, provided that R₄ is absent when        the atom to which it is bound forms part of a double bond;    -   R₅ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy, carbonyl,        oxycarbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicyoloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₅ and R₄ are taken together to        form a substituted or unsubstituted ring, provided that R₅ is        absent when the atom to which it is bound forms part of a double        bond;    -   R₆ and R₇ are each independently selected from the group        consisting of hydrogen, halo, cyano, heteroaryloxy, carbonyl,        oxycarbonyl, aminocarbonyl, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicyoloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₇ and R₅ are taken together to        form a substituted or unsubstituted ring, provided that R₇ is        absent when the atom to which it is bound forms part of a double        bond; and    -   R₈ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo (C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero (C₈₋₁₂)bicyclo aryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero (C₃₋₁₂)cyclo alkyl, (C₉₋₁₂)bicyclo        alkyl, hetero (C₃₋₁₂)bicyclo alkyl, (C₄₋₁₂)aryl,        hetero(C₁₋₁₀)aryl, (C₉₋₁₂)bicycloaryl and        hetero(C₄₋₁₂)bicycloaryl, each substituted or unsubstituted,        provided that R₈ is absent when the atom to which it is bound        forms part of a double bond.

In another embodiment, the intermediates comprise

-   -   wherein    -   X₁ and X₂ are each independently selected from the group        consisting of CR₆R₇, CO, CS and NR₈;    -   X₃ and X₄ are each independently selected from the group        consisting of CR₇ and N;    -   X₅ is selected from the group consisting of CR₆R₇, CS and NR₈;    -   R_(b), together with the O to which it is bound, is a leaving        group;    -   R₃ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, alkoxy, hydroxyalkoxy, aryloxy,        heteroaryloxy, carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, amino(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, provided that R₃ is absent when        the atom to which it is bound forms part of a double bond;    -   R₄ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, amido, (C₁₋₁₀)alkylamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, amido(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, provided that R₄ is absent when        the atom to which it is bound forms part of a double bond;    -   R₅ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy, carbonyl,        oxycarbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₅ and R₄ are taken together to        form a substituted or unsubstituted ring, provided that R₅ is        absent when the atom to which it is bound forms part of a double        bond;    -   R₆ and R₇ are each independently selected from the group        consisting of hydrogen, halo, cyano, heteroaryloxy, carbonyl,        oxycarbonyl, aminocarbonyl, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicyclo aryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₇ and R₅ are taken together to        form a substituted or unsubstituted ring, provided that R₇ is        absent when the atom to which it is bound forms part of a double        bond; and    -   R₈ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, provided that R₈ is absent when        the atom to which it is bound forms part of a double bond.

In still another embodiment, the intermediates comprise

-   -   wherein    -   R₃ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, alkoxy, hydroxyalkoxy, aryloxy,        heteroaryloxy, carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, amino(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, provided that R₃ is absent when        the atom to which it is bound forms part of a double bond; and    -   R₅ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy, carbonyl,        oxycarbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicyoloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₅ and R₄ are taken together to        form a substituted or unsubstituted ring, provided that R₅ is        absent when the atom to which it is bound forms part of a double        bond.

In yet another embodiment, the intermediates comprise

-   -   wherein    -   R_(b), together with the O to which it is bound, is a leaving        group;    -   R₃ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, alkoxy, hydroxyalkoxy, aryloxy,        heteroaryloxy, carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, amino(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, provided that R₃ is absent when        the atom to which it is bound forms part of a double bond; and    -   R₅ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy, carbonyl,        oxycarbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₅ and R₄ are taken together to        form a substituted or unsubstituted ring, provided that R₅ is        absent when the atom to which it is bound forms part of a double        bond.

In a further embodiment, the intermediates comprise

-   -   wherein    -   X₁ and X₂ are each independently selected from the group        consisting of CR₆R₇, CO, CS and NR₈;    -   X₃ and X₄ are each independently selected from the group        consisting of CR₇ and N;    -   X₅ is selected from the group consisting of CR₆R₇, CS and NR₈;    -   R₃ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, alkoxy, hydroxyalkoxy, aryloxy,        heteroaryloxy, carbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido,        imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, amino(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl, imino(C₁₋₃)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, provided that R₃ is absent when        the atom to which it is bound forms part of a double bond;    -   R₄ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, amido, (C₁₋₁₀)alkylamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        hydroxy(C₁₋₁₀)alkyl, amido(C₁₋₁₀)alkyl, carbonyl(C₁₋₁₀)alkyl,        thiocarbonyl(C₁₋₁₀)alkyl, sulfonyl(C₁₋₁₀)alkyl,        sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl, imino(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, provided that R₄ is absent when        the atom to which it is bound forms part of a double bond;    -   R₅ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, alkoxy, aryloxy, heteroaryloxy, carbonyl,        oxycarbonyl, amino, (C₁₋₁₀)alkylamino, sulfonamido, imino,        sulfonyl, sulfinyl, (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicyoloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₅ and R₄ are taken together to        form a substituted or unsubstituted ring, provided that R₅ is        absent when the atom to which it is bound forms part of a double        bond;    -   R₆ and R₇ are each independently selected from the group        consisting of hydrogen, halo, cyano, heteroaryloxy, carbonyl,        oxycarbonyl, aminocarbonyl, amino, (C₁₋₁₀)alkylamino,        sulfonamido, imino, sulfonyl, sulfinyl, (C₁₋₁₀)alkyl,        halo(C₁₋₁₀)alkyl, carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, amino (C₁₋₁₀)alkyl,        imino(C₁₋₃)alkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicyclo aryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicyoloaryl(C₁₋₅)alkyl, (C₃₋₁₂)cycloalkyl,        hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, or R₇ and R₅ are taken together to        form a substituted or unsubstituted ring, provided that R₇ is        absent when the atom to which it is bound forms part of a double        bond;    -   R₈ is selected from the group consisting of hydrogen, oxy,        hydroxy, carbonyloxy, (C₁₋₁₀)alkoxy, (C₄₋₁₂)aryloxy,        hetero(C₁₋₁₀)aryloxy, carbonyl, oxycarbonyl, amino,        (C₁₋₁₀)alkylamino, sulfonamido, imino, sulfonyl, sulfinyl,        (C₁₋₁₀)alkyl, halo(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,        carbonyl(C₁₋₁₀)alkyl, thiocarbonyl(C₁₋₁₀)alkyl,        sulfonyl(C₁₋₁₀)alkyl, sulfinyl(C₁₋₁₀)alkyl, (C₁₋₁₀)azaalkyl,        imino(C₁₋₁₀)alkyl, (C₃₋₁₂)cyclo alkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, aryl(C₁₋₁₀)alkyl,        hetero(C₁₋₁₀)aryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl(C₁₋₅)alkyl,        hetero(C₈₋₁₂)bicycloaryl(C₁₋₅)alkyl, hetero(C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₉₋₁₂)bicycloalkyl,        hetero(C₃₋₁₂)bicycloalkyl, (C₄₋₁₂)aryl, hetero(C₁₋₁₀)aryl,        (C₉₋₁₂)bicycloaryl and hetero(C₄₋₁₂)bicycloaryl, each        substituted or unsubstituted, provided that R₈ is absent when        the atom to which it is bound forms part of a double bond; and    -   X is halo.

In one variation of each of the above embodiments, X₁ is —CR₆═. Inanother variation, X₁ is —CR₆═ and R₆ is halo. In still anothervariation, X₁ is —CH═.

In yet another variation of each of the above embodiments andvariations, X₂ is CO. In a further variation of each of the aboveembodiments and variations, X₂ is —CR₆═.

In still a further variation of each of the above embodiments andvariations, X₃ is C.

In yet a further variation of each of the above embodiments andvariations, X₄ is C.

In another variation of each of the above embodiments and variations, X₅is —CR₆═. In still another variation of each of the above embodimentsand variations, X₅ is —CR₆═ and R₆ is halo and, more particularly,fluoro. In yet another variation of each of the above embodiments andvariations, X₅ is —CR₆═ and R₆ is a substituted or unsubstituted(C₁₋₅)alkyl. In a further variation of each of the above embodiments andvariations, X₅ is —CR₆═ and R₆ is a substituted or unsubstituted amino.In still a further variation of each of the above embodiments andvariations, X₅ is —CH═.

In yet a further variation of each of the above embodiments andvariations, L is a substituted or unsubstituted (C₁₋₁₀)alkylene. Inanother variation of each of the above embodiments and variations, L isa substituted or unsubstituted (C₁₋₃)alkylene.

In still another variation of each of the above embodiments andvariations, R₁ is selected from the group consisting of(C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, (C₄₋₁₂)aryl andhetero(C₁₋₁₀)aryl, each substituted or unsubstituted. In yet anothervariation of each of the above embodiments and variations, R₁ isselected from the group consisting of (C₄₋₁₂)aryl and hetero(C₁₋₁₀)aryl,each substituted or unsubstituted. In a further variation of each of theabove embodiments and variations, R₁ is a substituted or unsubstituted(C₄₋₁₂)aryl. In still a further variation of each of the aboveembodiments and variations, R₁ is a substituted or unsubstituted phenyl.In another variation of each of the above embodiments and variations, R₁is a substituted or unsubstituted 2-halophenyl. In still anothervariation of each of the above embodiments and variations, R₁ is asubstituted or unsubstituted 2,4-dihalophenyl. In yet another variationof each of the above embodiments and variations, R₁ is a substituted orunsubstituted 4-cyanophenyl. In another variation of each of the aboveembodiments and variations, R₁ is a substituted or unsubstituted2-halo-4-cyanophenyl. In yet a further variation of each of the aboveembodiments and variations, R₁ is a substituted or unsubstituted(C₉₋₁₂)bicycloaryl. In another variation of each of the aboveembodiments and variations, R₁ is a substituted or unsubstitutednaphthyl. In still another variation of each of the above embodimentsand variations, R₁ is a substituted or unsubstitutedhetero(C₄₋₁₂)bicycloaryl,

In yet another variation of each of the above embodiments andvariations, R₁ is substituted with one or more substituents selectedfrom the group consisting of hydrogen, halo, cyano, thio, alkoxy,(C₁₋₃)alkyl, hydroxy(C₁₋₃)alkyl and (C₃₋₈)cycloalkyl, each substitutedor unsubstituted. In a further variation of each of the aboveembodiments and variations, R₁ is substituted with one or moresubstituents selected from the group consisting of hydrogen, fluoro,chloro, bromo, iodo, cyano, methylthio, methoxy, trifluoromethoxy,methyl, ethyl, trifluoromethyl, ethynyl, n-propanolyl and cyclopropyl.

In still a further variation of each of the above embodiments andvariations, R₁ comprises:

-   -   wherein    -   R_(14a), R_(14b), R_(14c), R_(14d) and R_(14e) are each        independently selected from the group consisting of hydrogen,        halo, cyano, thio, alkoxy, (C₁₋₃)alkyl and hydroxy(C₁₋₃)alkyl,        each substituted or unsubstituted.

In yet a further variation of each of the above embodiments andvariations, the compound or process according to any one of claims 1-14and 19-42, wherein R₂ is hydrogen.

In another variation of each of the above embodiments and variations, R₃is absent. In still another variation of each of the above embodimentsand variations, R₃ is selected from the group consisting of hydrogen,hydroxy, (C₁₋₁₀)alkoxy, aminoalkoxy, (C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,amino (C₁₋₁₀)alkyl, cyclo amino (C₁₋₁₀)alkyl, (C₃₋₁₂)cyclo alkyl,hetero(C₃₋₁₂)cycloalkyl and hetero(C₁₋₁₀)aryl, each substituted orunsubstituted. In a further variation of each of the above embodimentsand variations, R₃ is a substituted or unsubstituted hydroxyalkyl. Instill a further variation of each of the above embodiments andvariations, R₃ is a substituted or unsubstituted hydroxyalkoxy. In yet afurther variation of each of the above embodiments and variations, R₃ isa substituted or unsubstituted aminoalkyl. In another variation of eachof the above embodiments and variations, R₃ is a substituted orunsubstituted arylalkyl. In still another variation of each of the aboveembodiments and variations, R₃ is a substituted or unsubstituted(C₁₋₁₀)alkyl. In yet another variation of each of the above embodimentsand variations, R₃ is a substituted or unsubstituted (C₃₋₆)cycloalkyl.In a further variation of each of the above embodiments and variations,R₃ is a substituted or unsubstituted aminoalkoxy. In still a furthervariation of each of the above embodiments and variations, R₃ is asubstituted or unsubstituted heterocycloalkylalkyl.

In yet another variation of each of the above embodiments andvariations, R₄ is absent. In a further variation of each of the aboveembodiments and variations, R₄ is selected from the group consisting of(C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl, amido(C₁₋₁₀)alkyl,(C₁₋₁₀)alkylcarbamido(C₁₋₁₀)alkyl and (C₁₋₁₀)alkylamido(C₁₋₁₀)alkyl,each substituted or unsubstituted. In a further variation of each of theabove embodiments and variations, R₄ is a substituted or unsubstituted(C₁₋₆)alkyl. In still a further variation of each of the aboveembodiments and variations, R₄ is a substituted or unsubstitutedaminoalkyl. In yet a further variation of each of the above embodimentsand variations, R₄ is a substituted or unsubstituted (C₁₋₆)alkylamido.In another variation of each of the above embodiments and variations, R₄is a substituted or unsubstituted hydroxy(C₁₋₆)alkyl.

In still a further variation of each of the above embodiments andvariations, R₅ is selected from the group consisting of hydrogen,(C₁₋₅)alkyl, amino (C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl and(C₃₋₁₂)cycloalkyl, each substituted or unsubstituted. In yet a furthervariation of each of the above embodiments and variations, R₅ isselected from the group consisting of (C₁₋₅)alkyl, amino(C₁₋₅)alkyl,carbonyl(C₁₋₅)alkyl, hydroxy(C₁₋₅)alkylalkoxy(C₁₋₅)alkyl,hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl and (C₃₋₈)cycloalkyl, eachsubstituted or unsubstituted. In another variation of each of the aboveembodiments and variations, R₅ is selected from the group consisting of(C₁₋₃)alkyl, (C₁₋₃)alkylamino(C₁₋₃)alkyl, di(C₁₋₃)alkylamino(C₁₋₃)alkyl,terahydrofuranyl(C₁₋₃)alkyl, pyrrolidinolyl(C₁₋₃)alkyl,thiazolidinyl(C₁₋₃)alkyl, hydroxyl-(C₁₋₃)alkan-one-yl,(C₁₋₃)alkoxy-(C₁₋₃)alkan-one-yl, (C₁₋₅)alkenyl, hydroxy(C₁₋₃)alkyl,N—(C₁₋₃)alkoxy-acetamido(C₁₋₃)alkyl,tetrahydro-2H-1,2-oxazine-one-yl-(C₁₋₃)alkyl,N—((C₁₋₃)alkylsulfinyl(C₁₋₃)alkoxy)-amino(C₁₋₃)alkyl,N—((C₁₋₃)alkylsulfinyl(C₁₋₃)alkyl)-amino(C₁₋₃)alkyl,(C₁₋₃)alkylsulfonyl(C₁₋₃)alkoxy(C₁₋₃)alkyl,imidazolidin-one-yl-(C₁₋₃)alkyl, dihydroxy-(C₁₋₅)alkyl andisoxazolidin-one-yl-(C₁₋₃)alkyl, each substituted or unsubstituted. Instill another variation of each of the above embodiments and variations,R₅ is selected from the group consisting of methyl, ethyl, propyl,n-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,methylaminomethyl, dimethylaminomethyl, terahydrofuranylmethyl,terahydrofuranylethyl, pyrrolidinolylmethyl, thiazolidinylmethyl,thiazolidinylethyl, hydroxyl-propan-one-yl, methoxy-propan-one-yl,butenyl, hydroxybutanyl, N-methoxy-acetamidomethyl,tetrahydro-2H-1,2-oxazine-one-yl-methyl,N-(methylsulfinylethoxy)-aminomethyl,N-(methylsulfinylpropyl)-aminomethyl, methylsulfonylethoxymethyl,imidazolidin-one-yl-ethyl, dihydroxy-butanyl andisoxazolidin-one-yl-methyl. In a further variation of each of the aboveembodiments and variations, R₅ is a substituted or unsubstituted(C₁₋₆)alkyl.

In yet another variation of each of the above embodiments andvariations, R₆ is selected from the group consisting of hydrogen, halo,amino and (C₁₋₅)alkyl, each substituted or unsubstituted. In stillanother variation of each of the above embodiments and variations, R₆ isa halo and, more particularly, chloro or fluoro. In yet anothervariation of each of the above embodiments and variations, R₆ is asubstituted or unsubstituted (C₁₋₅)alkyl and, mofre particularly,methyl.

In a further variation of each of the above embodiments and variations,R₇ is absent. In still a further variation of each of the aboveembodiments and variations, R₇ is selected from the group consisting ofhydrogen and a substituted or unsubstituted (C₁₋₅)alkyl.

In yet a further variation of each of the above embodiments andvariations, R₈ is absent.

In another variation of each of the above embodiments and variations, R₉is selected from the group consisting of hydrogen, (C₁₋₁₀)alkoxy,hydroxy(C₁₋₁₀)alkoxy, (C₁₋₁₀)alkyl, hydroxy(C₁₋₁₀)alkyl,amino(C₁₋₁₀)alkyl and hetero(C₃₋₁₂)cycloalkyl(C₁₋₁₀)alkyl, eachsubstituted or unsubstituted.

In still another variation of each of the above embodiments andvariations, R₁₀ is selected from the group consisting of hydroxl, amino,hydroxy(C₁₋₁₀)alkyl, (C₃₋₁₂)cycloalkyl and hetero(C₃₋₁₂)cycloalkyl, eachsubstituted or unsubstituted.

In yet another variation of each of the above embodiments andvariations, R₁₁ is selected from the group consisting of hydrogen and asubstituted or unsubstituted (C₁₋₅)alkyl. In a further variation of eachof the above embodiments and variations, R₁₁ is hydrogen.

In still a further variation of each of the above embodiments andvariations, n is selected from the group consisting of 1, 2 and 3. Inyet a further variation of each of the above embodiments and variations,n is 1. In another variation of each of the above embodiments andvariations, n is 2.

In still another variation of each of the above embodiments andvariations, each R₁₂ is independently selected from the group consistingof hydrogen, hydroxl, (C₁₋₅)alkyl and hydroxy(C₁₋₅)alkyl, eachsubstituted or unsubstituted. In yet another variation of each of theabove embodiments and variations, R₁₂ is hydrogen. In a furthervariation of each of the above embodiments and variations, R₁₂ ishydroxy.

In still a further variation of each of the above embodiments andvariations, each R₁₃ is independently selected from the group consistingof hydrogen, hydroxl, (C₁₋₅)alkyl and hydroxy(C₁₋₅)alkyl, eachsubstituted or unsubstituted. In yet a further variation of each of theabove embodiments and variations, R₁₃ is hydrogen.

In another variation of each of the above embodiments and variations,R₁₄ is selected from the group consisting of hydrogen, halo, cyano,carbonyl, (C₁₋₅)alkyl and (C₃₋₁₂)cycloalkyl, each substituted orunsubstituted. In still another variation of each of the aboveembodiments and variations, R₁₄ is hydrogen. In yet another variation ofeach of the above embodiments and variations, R₁₄ is halo.

In a further variation of each of the above embodiments and variations,R_(14a) is selected from the group consisting of hydrogen, halo, and asubstituted or unsubstituted (C₁₋₅)alkyl.

In still a further variation of each of the above embodiments andvariations, R_(14b) is selected from the group consisting of hydrogen,halo, carbonyl, alkoxy, (C₁₋₃)alkyl and (C₃₋₁₂)cycloalkyl, eachsubstituted or unsubstituted.

In yet a further variation of each of the above embodiments andvariations, R_(14c) is selected from the group consisting of hydrogen,halo, cyano, thio, (C₁₋₃)alkyl and hydroxy(C₁₋₃)alkyl, each substitutedor unsubstituted.

In another variation of each of the above embodiments and variations,R_(14d) is selected from the group consisting of hydrogen, halo,carbonyl, alkoxy, (C₁₋₃)alkyl and (C₃₋₁₂)cycloalkyl, each substituted orunsubstituted.

In still another variation of each of the above embodiments andvariations, R_(14e) is selected from the group consisting of hydrogen,halo, carbonyl, alkoxy, (C₁₋₃)alkyl and (C₃₋₁₂)cycloalkyl, eachsubstituted or unsubstituted.

In yet another variation of each of the above embodiments andvariations, R₁₅ is hydrogen. In a further variation of each of the aboveembodiments and variations, R₁₅ is hydroxy.

In still a further variation of each of the above embodiments andvariations, R₁₆ is hydrogen.

In yet a further variation of each of the above embodiments andvariations, p is selected from the group consisting of 1, 2 and 3.

In another variation of each of the above embodiments and variations,R₁₇ is hydroxy.

In still another variation of each of the above embodiments andvariations, R_(a) is ethyl.

In yet another variation of each of the above embodiments andvariations, R_(b) is selected from the group consisting of halo andtosyl.

Particular examples of compounds according to the present inventioninclude, but are not limited to:

-   5-(2-fluoro-4-iodophenylamino)-3,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   5-(2-fluoro-4-iodophenylamino)-3-(2-hydroxyethyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   methyl    2-(5-(2-fluoro-4-iodophenylamino)-8-methyl-4,7-dioxo-7,8-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)acetate;-   5-(2-fluoro-4-iodophenylamino)-3,6,8-trimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   (S)-3-(2,3-Dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   (R)-3-(2,3-Dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   (S)-6-Chloro-3-(2,3-dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   (R)-3-(2,3-Dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   (S)-5-(4-Bromo-2-fluorophenylamino)-3-(2,3-dihydroxypropyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   (R)-5-(4-Bromo-2-fluorophenylamino)-3-(2,3-dihydroxypropyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   5-(4-Bromo-2-fluorophenylamino)-3-(2-hydroxyethyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   5-(2-Fluoro-4-iodophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   (S)-3-(2,3-Dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   5-(2-Fluoro-4-iodophenylamino)-3-(2-hydroxyethyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   5-(2-Fluorophenylamino)-3-(2-hydroxyethyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   (R)-3-(2,3-Dihydroxypropyl)-5-(4-ethynyl-2-fluorophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   6-Fluoro-5-(2-fluoro-4-iodophenylamino)-3-(2-hydroxyethyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   (R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   (S)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   (R)-5-(4-Bromo-2-fluorophenylamino)-3-(2,3-dihydroxypropyl)-6-fluoro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   (S)-3-(2,3-Dihydroxypropyl)-5-(4-ethynyl-2-fluorophenylamino)-6-fluoro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   (R)-3-(2,3-dihydroxypropyl)-5-(4-ethynyl-2-fluorophenylamino)-6-fluoro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   (R)—N-(4-(3-(2,3-Dihydroxypropyl)-6-fluoro-8-methyl-4,7-dioxo-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidin-5-ylamino)-3-fluorophenyl)methanesulfonamide;-   3-(1,3-Dihydroxypropan-2-yl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   3-(1,3-Dihydroxypropan-2-yl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   5-(2-Fluoro-4-iodophenylamino)-3-(2-hydroxyethoxy)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   (R)-3-(2,3-Dihydroxypropoxy)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   (R)-3-(2,3-Dihydroxypropoxy)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   (R)-5-(4-Bromo-2-fluorophenylamino)-6-chloro-3-(2,3-dihydroxypropyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   6-Chloro-5-(2-fluoro-4-iodophenylamino)-3-(2-hydroxyethyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   5-(2-Fluoro-4-iodophenylamino)-3-(3-hydroxypropyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   6-Chloro-5-(2-fluoro-4-iodophenylamino)-3-(3-hydroxypropyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   5-(4-Bromo-2-fluorophenylamino)-3-(3-hydroxypropyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   5-(4-Bromo-2-fluorophenylamino)-6-chloro-3-(3-hydroxypropyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   5-(4-Bromo-2-chlorophenylamino)-3-(3-hydroxypropyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   5-(4-Bromo-2-chlorophenylamino)-6-chloro-3-(3-hydroxypropyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   3-(2-(Dimethylamino)ethyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   5-(2-Fluoro-4-iodophenylamino)-3-(2-hydroxypropyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   (S)-3-(2,4-Dihydroxybutyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   6-Chloro-5-(2-fluoro-4-iodophenylamino)-3-(2-hydroxypropyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   (S)-5-(4-Bromo-2-fluorophenylamino)-3-(2,3-dihydroxypropyl)-6-fluoro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   3-Benzyl-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   3-(1,3-Dihydroxypropan-2-yl)-5-(2-fluoro-4-iodophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   (S)-3-(2,3-Dihydroxypropyl)-5-(4-ethynyl-2-fluorophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   2-fluoro-5-(2-fluoro-4-iodophenylamino)-3,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   5-(2-fluoro-4-iodophenylamino)-3,8-dimethyl-2-(methylamino)pyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   5-(2-fluoro-4-iodophenylamino)-2,3,8-trimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   5-(2-fluoro-4-iodophenylamino)-1,8-dimethylpyrido[2,3-d]pyrimidine-4,7(1H,8H)-dione;-   3-(5-(2-fluoro-4-iodophenylamino)-8-methyl-4,7-dioxo-7,8-dihydropyrido[2,3-d]pyrimidin-1(4H)-yl)propanamide;-   N-(2-(5-(2-fluoro-4-iodophenylamino)-8-methyl-4,7-dioxo-7,8-dihydropyrido[2,3-d]pyrimidin-1(4H)-yl)ethyl)acetamide;-   5-(2-fluoro-4-iodophenylamino)-1-(2-hydroxyethyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(1H,8H)-dione;-   2-(5-(2-fluoro-4-iodophenylamino)-8-methyl-4,7-dioxo-7,8-dihydropyrido[2,3-d]pyrimidin-1(4H)-yl)-N-methylacetamide;-   1-ethyl-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(1H,8H)-dione;-   3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   (S)-5-(4-bromo-2-chlorophenylamino)-3-(2,3-dihydroxypropyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   (S)-3-(2,3-dihydroxypropoxy)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   3-(2-aminoethoxy)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   3-(3-aminopropyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   3-(2-aminoethyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   5-(2-fluoro-4-iodophenylamino)-8-methyl-3-(pyrrolidin-3-ylmethyl)pyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   (S)-5-(2-chloro-4-iodophenylamino)-3-(2,3-dihydroxypropyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   (S)-5-(4-bromo-2-fluorophenylamino)-3-(2,3-dihydroxypropyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   (S)-3-(2,3-dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-6,8-dimethylpyrido[4,3-d]pyrimidine-4,7(3H,6H)-dione;-   (R)-3-(2,3-dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-6,8-dimethylpyrido[4,3-d]pyrimidine-4,7(3H,6H)-dione;-   5-(2-fluoro-4-iodophenylamino)-3-(2-hydroxyethoxy)-6,8-dimethylpyrido[4,3-d]pyrimidine-4,7(3H,6H)-dione;-   5-(2-fluoro-4-iodophenylamino)-3-(3-hydroxypropyl)-6,8-dimethylpyrido[4,3-d]pyrimidine-4,7(3H,6H)-dione;    and-   5-(2-fluoro-4-iodophenylamino)-3-(2-hydroxyethyl)-6,8-dimethylpyrido[4,3-d]pyrimidine-4,7(3H,6H)-dione.

In addition, particular examples of compounds according to the presentinvention include, but are not limited to:

-   (R)-3-(2,3-Dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   (S)-3-(2,3-Dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   (R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   (S)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   (S)-3-(2,3-Dihydroxypropyl)-5-(4-ethynyl-2-fluorophenylamino)-6-fluoro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;-   (R)-3-(2,3-dihydroxypropyl)-5-(4-ethynyl-2-fluorophenylamino)-6-fluoro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,    8H)-dione;-   3-(1,3-Dihydroxypropan-2-yl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,    8H)-dione; and-   (R)-3-(2,3-Dihydroxypropoxy)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,    8H)-dione.

It is noted that the compounds of the present invention may be in theform of a pharmaceutically acceptable salt, biohydrolyzable ester,biohydrolyzable amide, biohydrolyzable carbamate, solvate, hydrate orprodrug thereof. For example, the compound optionally comprises asubstituent that is convertible in vivo to a different substituent suchas hydrogen.

It is further noted that the compound may be present as a mixture ofstereoisomers, or the compound may be present as a single stereoisomer.

In another of its aspects, there is provided a pharmaceuticalcomposition comprising as an active ingredient a compound according toany one of the above embodiments and variations. In one particularvariation, the composition is a solid formulation adapted for oraladministration. In another particular variation, the composition is aliquid formulation adapted for oral administration. In yet anotherparticular variation, the composition is a tablet. In still anotherparticular variation, the composition is a liquid formulation adaptedfor parenteral administration.

In another of its aspects, there is provided a pharmaceuticalcomposition comprising a compound according to any one of the aboveembodiments and variations, wherein the composition is adapted foradministration by a route selected from the group consisting of orally,parenterally, intraperitoneally, intravenously, intraarterially,transdermally, sublingually, intramuscularly, rectally, transbuccally,intranasally, liposomally, via inhalation, vaginally, intraoccularly,via local delivery (for example by catheter or stent), subcutaneously,intraadiposally, intraarticularly, and intrathecally.

In yet another of its aspects, there is provided a kit comprising acompound of any one of the above embodiments and variations; andinstructions which comprise one or more forms of information selectedfrom the group consisting of indicating a disease state for which thecomposition is to be administered, storage information for thecomposition, dosing information and instructions regarding how toadminister the composition. In one particular variation, the kitcomprises the compound in a multiple dose form.

In still another of its aspects, there is provided an article ofmanufacture comprising a compound of any one of the above embodimentsand variations; and packaging materials. In one variation, the packagingmaterial comprises a container for housing the compound. In oneparticular variation, the container comprises a label indicating one ormore members of the group consisting of a disease state for which thecompound is to be administered, storage information, dosing informationand/or instructions regarding how to administer the compound. In anothervariation, the article of manufacture comprises the compound in amultiple dose form.

In a further of its aspects, there is provided a therapeutic methodcomprising administering a compound of any one of the above embodimentsand variations to a subject.

In another of its aspects, there is provided a method of inhibiting aMitogen-Activated Protein Kinase (MEK) comprising contacting the MEKwith a compound of any one of the above embodiments and variations.

In yet another of its aspects, there is provided a method of inhibitinga Mitogen-Activated Protein Kinase (MEK) comprising causing a compoundof any one of the above embodiments and variations to be present in asubject in order to inhibit the MEK in vivo.

In a further of its aspects, there is provided a method of inhibitingMitogen-Activated Protein Kinase (MEK) comprising administering a firstcompound to a subject that is converted in vivo to a second compoundwherein the second compound inhibits the MEK in vivo, the secondcompound being a compound according to any one of the above embodimentsand variations.

In another of its aspects, there is provided a method of treating adisease state for which a Mitogen-Activated Protein Kinase (MEK)possesses activity that contributes to the pathology and/or symptomologyof the disease state, the method comprising causing a compound of anyone of the above embodiments and variations to be present in a subjectin a therapeutically effective amount for the disease state.

In yet another of its aspects, there is provided a method of treating adisease state for which a Mitogen-Activated Protein Kinase (MEK)possesses activity that contributes to the pathology and/or symptomologyof the disease state, the method comprising administering a compound ofany one of the above embodiments and variations to a subject, whereinthe compound is present in the subject in a therapeutically effectiveamount for the disease state.

In a further of its aspects, there is provided a method of treating adisease state for which a Mitogen-Activated Protein Kinase (MEK)possesses activity that contributes to the pathology and/or symptomologyof the disease state, the method comprising administering a firstcompound to a subject that is converted in vivo to a second compoundwherein the second compound inhibits the MEK in vivo. It is noted thatthe compounds of the present invention may be the first or secondcompounds.

In one variation of each of the above methods the disease state isselected from the group consisting of cancerous hyperproliferativedisorders (e.g., brain, lung, squamous cell, bladder, gastric,pancreatic, breast, head, neck, renal, kidney, ovarian, prostate,colorectal, epidermoid, esophageal, testicular, gynecological or thyroidcancer); non-cancerous hyperproliferative disorders (e.g., benignhyperplasia of the skin (e.g., psoriasis), restenosis, and benignprostatic hypertrophy (BPH)); pancreatitis; kidney disease; pain;preventing blastocyte implantation; treating diseases related tovasculogenesis or angiogenesis (e.g., tumor angiogenesis, acute andchronic inflammatory disease such as rheumatoid arthritis,atherosclerosis, inflammatory bowel disease, skin diseases such aspsoriasis, exzema, and scleroderma, diabetes, diabetic retinopathy,retinopathy of prematurity, age-related macular degeneration,hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast,lung, pancreatic, prostate, colon and epidermoid cancer); asthma;neutrophil chemotaxis (e.g., reperfusion injury in myocardial infarctionand stroke and inflammatory arthritis); septic shock; T-cell mediateddiseases where immune suppression would be of value (e.g., theprevention of organ transplant rejection, graft versus host disease,lupus erythematosus, multiple sclerosis, and rheumatoid arthritis);atherosclerosis; inhibition of keratinocyte responses to growth factorcocktails; chronic obstructive pulmonary disease (COPD) and otherdiseases.

In another variation of each of the above methods, the Mitogen-ActivatedProtein Kinase (MEK) is MEK1. In still another variation of each of theabove methods, the Mitogen-Activated Protein Kinase (MEK) is MEK2.

In another of its aspects, there is provided a method of inhibiting anExtracellular Regulated Kinase (ERK) comprising contacting the ERK witha compound of any of the above embodiments and variations.

In still another of its aspects, there is provided a method ofinhibiting Extracellular Regulated Kinase (ERK) comprising causing acompound of any of the above embodiments and variations to be present ina subject in order to inhibit the ERK in vivo.

In yet another of its aspects, there is provided a method of inhibitingExtracellular Regulated Kinase (ERK) comprising administering a firstcompound to a subject that is converted in vivo to a second compoundwherein the second compound inhibits the ERK in vivo, the secondcompound being a compound according to any of the above embodiments andvariations.

In one variation of the above methods, the Extracellular RegulatedKinase (ERK) is ERK1. In another variation of the above methods, theExtracellular Regulated Kinase (ERK) is ERK2.

In another of its aspects, there is provided a method of treating adisease state for which a mutation in the B-Raf gene contributes to thepathology and/or symptomology of the disease state including, forexample, melanomas, lung cancer, colon cancer and other tumor types.

In still another of its aspects, the present invention relates to theuse of a compound of any of the above embodiments and variations as amedicament.

In yet another of its aspects, the present invention relates to the useof a compound according to any one of the above embodiments andvariations in the manufacture of a medicament for inhibiting aMitogen-Activated Protein Kinase (MEK).

In a further of its aspects, the present invention relates to the use ofa compound according to any one of the above embodiments and variationsin the manufacture of a medicament for treating a disease state forwhich a Mitogen-Activated Protein Kinase (MEK) possesses activity thatcontributes to the pathology and/or symptomology of the disease state.

In still a further of its aspects, the present invention relates to theuse of a compound according to any one of the above embodiments andvariations in the manufacture of a medicament for treatinghyperproliferative disorders; pancreatitis; kidney disease; pain;diseases involving blastocyte implantation; diseases related tovasculogenesis or angiogenesis; asthma; neutrophil chemotaxis; andseptic shock.

Salts, Hydrates, and Prodrugs of MEK Inhibitors

It should be recognized that the compounds of the present invention maybe present and optionally administered in the form of salts, hydratesand prodrugs that are converted in vivo into the compounds of thepresent invention. For example, it is within the scope of the presentinvention to convert the compounds of the present invention into and usethem in the form of their pharmaceutically acceptable salts derived fromvarious organic and inorganic acids and bases in accordance withprocedures well known in the art.

When the compounds of the present invention possess a free base form,the compounds can be prepared as a pharmaceutically acceptable acidaddition salt by reacting the free base form of the compound with apharmaceutically acceptable inorganic or organic acid, e.g.,hydrohalides such as hydrochloride, hydrobromide, hydroiodide; othermineral acids and their corresponding salts such as sulfate, nitrate,phosphate, etc.; and alkyl and monoarylsulfonates such asethanesulfonate, toluenesulfonate and benzenesulfonate; and otherorganic acids and their corresponding salts such as acetate, tartrate,maleate, succinate, citrate, benzoate, salicylate and ascorbate. Furtheracid addition salts of the present invention include, but are notlimited to: adipate, alginate, arginate, aspartate, bisulfate,bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate,chloride, chlorobenzoate, cyclopentanepropionate, digluconate,dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, fumarate,galacterate (from mucic acid), galacturonate, glucoheptonate, gluconate,glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate,hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isethionate, iso-butyrate, lactate,lactobionate, malate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate and phthalate. It should be recognized that the free baseforms will typically differ from their respective salt forms somewhat inphysical properties such as solubility in polar solvents, but otherwisethe salts are equivalent to their respective free base forms for thepurposes of the present invention.

When the compounds of the present invention possess a free acid form, apharmaceutically acceptable base addition salt can be prepared byreacting the free acid form of the compound with a pharmaceuticallyacceptable inorganic or organic base. Examples of such bases are alkalimetal hydroxides including potassium, sodium and lithium hydroxides;alkaline earth metal hydroxides such as barium and calcium hydroxides;alkali metal alkoxides, e.g., potassium ethanolate and sodiumpropanolate; and various organic bases such as ammonium hydroxide,piperidine, diethanolamine and N-methylglutamine. Also included are thealuminum salts of the compounds of the present invention. Further basesalts of the present invention include, but are not limited to: copper,ferric, ferrous, lithium, magnesium, manganic, manganous, potassium,sodium and zinc salts. Organic base salts include, but are not limitedto, salts of primary, secondary and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, e.g., arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine),dicyclohexylamine, diethanolamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, iso-propylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine and tris-(hydroxymethyl)-methylamine(tromethamine). It should be recognized that the free acid forms willtypically differ from their respective salt forms somewhat in physicalproperties such as solubility in polar solvents, but otherwise the saltsare equivalent to their respective free acid forms for the purposes ofthe present invention.

Compounds of the present invention that comprise basicnitrogen-containing groups may be quaternized with such agents as (C₁₋₄)alkyl halides, e.g., methyl, ethyl, iso-propyl and tert-butyl chlorides,bromides and iodides; di (C₁₋₄) alkyl sulfates, e.g., dimethyl, diethyland diamyl sulfates; (C₁₀₋₁₈) alkyl halides, e.g., decyl, dodecyl,lauryl, myristyl and stearyl chlorides, bromides and iodides; and aryl(C₁₋₄) alkyl halides, e.g., benzyl chloride and phenethyl bromide. Suchsalts permit the preparation of both water-soluble and oil-solublecompounds of the present invention.

N-oxides of compounds according to the present invention can be preparedby methods known to those of ordinary skill in the art. For example,N-oxides can be prepared by treating an unoxidized form of the compoundwith an oxidizing agent (e.g., trifluoroperacetic acid, permaleic acid,perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, or thelike) in a suitable inert organic solvent (e.g., a halogenatedhydrocarbon such as dichloromethane) at approximately 0° C.Alternatively, the N-oxides of the compounds can be prepared from theN-oxide of an appropriate starting material.

Prodrug derivatives of compounds according to the present invention canbe prepared by modifying substituents of compounds of the presentinvention that are then converted in vivo to a different substituent. Itis noted that in many instances, the prodrugs themselves also fallwithin the scope of the range of compounds according to the presentinvention. For example, prodrugs can be prepared by reacting a compoundwith a carbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate,para-nitrophenyl carbonate, or the like) or an acylating agent. Furtherexamples of methods of making prodrugs are described in Saulnier et al.(1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985.

Protected derivatives of compounds of the present invention can also bemade. Examples of techniques applicable to the creation of protectinggroups and their removal can be found in T. W. Greene, Protecting Groupsin Organic Synthesis, 3^(rd) edition, John Wiley & Sons, Inc. 1999.

Compounds of the present invention may also be conveniently prepared, orformed during the process of the invention, as solvates (e.g.,hydrates). Hydrates of compounds of the present invention may beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

A “pharmaceutically acceptable salt”, as used herein, is intended toencompass any compound according to the present invention that isutilized in the form of a salt thereof, especially where the saltconfers on the compound improved pharmacokinetic properties as comparedto the free form of compound or a different salt form of the compound.The pharmaceutically acceptable salt form may also initially conferdesirable pharmacokinetic properties on the compound that it did notpreviously possess, and may even positively affect the pharmacodynamicsof the compound with respect to its therapeutic activity in the body. Anexample of a pharmacokinetic property that may be favorably affected isthe manner in which the compound is transported across cell membranes,which in turn may directly and positively affect the absorption,distribution, biotransformation and excretion of the compound. While theroute of administration of the pharmaceutical composition is important,and various anatomical, physiological and pathological factors cancritically affect bioavailability, the solubility of the compound isusually dependent upon the character of the particular salt formthereof, which it utilized. One of skill in the art will appreciate thatan aqueous solution of the compound will provide the most rapidabsorption of the compound into the body of a subject being treated,while lipid solutions and suspensions, as well as solid dosage forms,will result in less rapid absorption of the compound.

Compositions Comprising MEK Inhibitors

A wide variety of compositions and administration methods may be used inconjunction with the compounds of the present invention. Suchcompositions may include, in addition to the compounds of the presentinvention, conventional pharmaceutical excipients, and otherconventional, pharmaceutically inactive agents. Additionally, thecompositions may include active agents in addition to the compounds ofthe present invention. These additional active agents may includeadditional compounds according to the invention, and/or one or moreother pharmaceutically active agents.

The compositions may be in gaseous, liquid, semi-liquid or solid form,formulated in a manner suitable for the route of administration to beused. For oral administration, capsules and tablets are typically used.For parenteral administration, reconstitution of a lyophilized powder,prepared as described herein, is typically used.

Compositions comprising compounds of the present invention may beadministered or coadministered orally, parenterally, intraperitoneally,intravenously, intraarterially, transdermally, sublingually,intramuscularly, rectally, transbuccally, intranasally, liposomally, viainhalation, vaginally, intraoccularly, via local delivery (for exampleby catheter or stent), subcutaneously, intraadiposally,intraarticularly, or intrathecally. The compounds and/or compositionsaccording to the invention may also be administered or coadministered inslow release dosage forms.

The MEK inhibitors and compositions comprising them may be administeredor coadministered in any conventional dosage form. Co-administration inthe context of this invention is intended to mean the administration ofmore than one therapeutic agent, one of which includes a MEK inhibitor,in the course of a coordinated treatment to achieve an improved clinicaloutcome. Such co-administration may also be coextensive, that is,occurring during overlapping periods of time.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application may optionally include one or more of thefollowing components: a sterile diluent, such as water for injection,saline solution, fixed oil, polyethylene glycol, glycerine, propyleneglycol or other synthetic solvent; antimicrobial agents, such as benzylalcohol and methyl parabens; antioxidants, such as ascorbic acid andsodium bisulfite; chelating agents, such as ethylenediaminetetraaceticacid (EDTA); buffers, such as acetates, citrates and phosphates; agentsfor the adjustment of tonicity such as sodium chloride or dextrose, andagents for adjusting the acidity or alkalinity of the composition, suchas alkaline or acidifying agents or buffers like carbonates,bicarbonates, phosphates, hydrochloric acid, and organic acids likeacetic and citric acid. Parenteral preparations may optionally beenclosed in ampules, disposable syringes or single or multiple dosevials made of glass, plastic or other suitable material.

When compounds according to the present invention exhibit insufficientsolubility, methods for solubilizing the compounds may be used. Suchmethods are known to those of skill in this art, and include, but arenot limited to, using cosolvents, such as dimethylsulfoxide (DMSO),using surfactants, such as TWEEN, or dissolution in aqueous sodiumbicarbonate. Derivatives of the compounds, such as prodrugs of thecompounds may also be used in formulating effective pharmaceuticalcompositions.

Upon mixing or adding compounds according to the present invention to acomposition, a solution, suspension, emulsion or the like may be formed.The form of the resulting composition will depend upon a number offactors, including the intended mode of administration, and thesolubility of the compound in the selected carrier or vehicle. Theeffective concentration needed to ameliorate the disease being treatedmay be empirically determined.

Compositions according to the present invention are optionally providedfor administration to humans and animals in unit dosage forms, such astablets, capsules, pills, powders, dry powders for inhalers, granules,sterile parenteral solutions or suspensions, and oral solutions orsuspensions, and oil-water emulsions containing suitable quantities ofthe compounds, particularly the pharmaceutically acceptable salts,preferably the sodium salts, thereof. The pharmaceuticallytherapeutically active compounds and derivatives thereof are typicallyformulated and administered in unit-dosage forms or multiple-dosageforms. Unit-dose forms, as used herein, refers to physically discreteunits suitable for human and animal subjects and packaged individuallyas is known in the art. Each unit-dose contains a predetermined quantityof the therapeutically active compound sufficient to produce the desiredtherapeutic effect, in association with the required pharmaceuticalcarrier, vehicle or diluent. Examples of unit-dose forms includeampoules and syringes individually packaged tablet or capsule. Unit-doseforms may be administered in fractions or multiples thereof. Amultiple-dose form is a plurality of identical unit-dosage formspackaged in a single container to be administered in segregatedunit-dose form. Examples of multiple-dose forms include vials, bottlesof tablets or capsules or bottles of pint or gallons. Hence, multipledose form is a multiple of unit-doses that are not segregated inpackaging.

In addition to one or more compounds according to the present invention,the composition may comprise: a diluent such as lactose, sucrose,dicalcium phosphate, or carboxymethylcellulose; a lubricant, such asmagnesium stearate, calcium stearate and talc; and a binder such asstarch, natural gums, such as gum acaciagelatin, glucose, molasses,polyvinylpyrrolidine, celluloses and derivatives thereof, povidone,crospovidones and other such binders known to those of skill in the art.Liquid pharmaceutically administrable compositions can, for example, beprepared by dissolving, dispersing, or otherwise mixing an activecompound as defined above and optional pharmaceutical adjuvants in acarrier, such as, for example, water, saline, aqueous dextrose,glycerol, glycols, ethanol, and the like, to form a solution orsuspension. If desired, the pharmaceutical composition to beadministered may also contain minor amounts of auxiliary substances suchas wetting agents, emulsifying agents, or solubilizing agents, pHbuffering agents and the like, for example, acetate, sodium citrate,cyclodextrine derivatives, sorbitan monolaurate, triethanolamine sodiumacetate, triethanolamine oleate, and other such agents. Actual methodsof preparing such dosage forms are known in the art, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15thEdition, 1975. The composition or formulation to be administered will,in any event, contain a sufficient quantity of a inhibitor of thepresent invention to reduce MEK activity in vivo, thereby treating thedisease state of the subject.

Dosage forms or compositions may optionally comprise one or morecompounds according to the present invention in the range of 0.005% to100% (weight/weight) with the balance comprising additional substancessuch as those described herein. For oral administration, apharmaceutically acceptable composition may optionally comprise any oneor more commonly employed excipients, such as, for examplepharmaceutical grades of mannitol, lactose, starch, magnesium stearate,talcum, cellulose derivatives, sodium crosscarmellose, glucose, sucrose,magnesium carbonate, sodium saccharin, talcum. Such compositions includesolutions, suspensions, tablets, capsules, powders, dry powders forinhalers and sustained release formulations, such as, but not limitedto, implants and microencapsulated delivery systems, and biodegradable,biocompatible polymers, such as collagen, ethylene vinyl acetate,polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid andothers. Methods for preparing these formulations are known to thoseskilled in the art. The compositions may optionally contain 0.01%-100%(weight/weight) of one or more MEK inhibitors, optionally 0.1-95%, andoptionally 1-95%.

Salts, preferably sodium salts, of the inhibitors may be prepared withcarriers that protect the compound against rapid elimination from thebody, such as time release formulations or coatings. The formulationsmay further include other active compounds to obtain desiredcombinations of properties.

Formulations for Oral Administration

Oral pharmaceutical dosage forms may be as a solid, gel or liquid.Examples of solid dosage forms include, but are not limited to tablets,capsules, granules, and bulk powders. More specific examples of oraltablets include compressed, chewable lozenges and tablets that may beenteric-coated, sugar-coated or film-coated. Examples of capsulesinclude hard or soft gelatin capsules. Granules and powders may beprovided in non-effervescent or effervescent forms. Each may be combinedwith other ingredients known to those skilled in the art.

In certain embodiments, compounds according to the present invention areprovided as solid dosage forms, preferably capsules or tablets. Thetablets, pills, capsules, troches and the like may optionally containone or more of the following ingredients, or compounds of a similarnature: a binder; a diluent; a disintegrating agent; a lubricant; aglidant; a sweetening agent; and a flavoring agent.

Examples of binders that may be used include, but are not limited to,microcrystalline cellulose, gum tragacanth, glucose solution, acaciamucilage, gelatin solution, sucrose, and starch paste.

Examples of lubricants that may be used include, but are not limited to,talc, starch, magnesium or calcium stearate, lycopodium and stearicacid.

Examples of diluents that may be used include, but are not limited to,lactose, sucrose, starch, kaolin, salt, mannitol, and dicalciumphosphate.

Examples of glidants that may be used include, but are not limited to,colloidal silicon dioxide.

Examples of disintegrating agents that may be used include, but are notlimited to, crosscarmellose sodium, sodium starch glycolate, alginicacid, corn starch, potato starch, bentonite, methylcellulose, agar andcarboxymethylcellulose.

Examples of coloring agents that may be used include, but are notlimited to, any of the approved certified water-soluble FD and C dyes,mixtures thereof; and water insoluble FD and C dyes suspended on aluminahydrate.

Examples of sweetening agents that may be used include, but are notlimited to, sucrose, lactose, mannitol and artificial sweetening agentssuch as sodium cyclamate and saccharin, and any number of spray-driedflavors.

Examples of flavoring agents that may be used include, but are notlimited to, natural flavors extracted from plants such as fruits andsynthetic blends of compounds that produce a pleasant sensation, suchas, but not limited to peppermint and methyl salicylate.

Examples of wetting agents that may be used include, but are not limitedto, propylene glycol monostearate, sorbitan monooleate, diethyleneglycol monolaurate, and polyoxyethylene lauryl ether.

Examples of anti-emetic coatings that may be used include, but are notlimited to, fatty acids, fats, waxes, shellac, ammoniated shellac andcellulose acetate phthalates.

Examples of film coatings that may be used include, but are not limitedto, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethyleneglycol 4000 and cellulose acetate phthalate.

If oral administration is desired, the salt of the compound mayoptionally be provided in a composition that protects it from the acidicenvironment of the stomach. For example, the composition can beformulated in an enteric coating that maintains its integrity in thestomach and releases the active compound in the intestine. Thecomposition may also be formulated in combination with an antacid orother such ingredient.

When the dosage unit form is a capsule, it may optionally additionallycomprise a liquid carrier such as a fatty oil. In addition, dosage unitforms may optionally additionally comprise various other materials thatmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents.

Compounds according to the present invention may also be administered asa component of an elixir, suspension, syrup, wafer, sprinkle, chewinggum or the like. A syrup may optionally comprise, in addition to theactive compounds, sucrose as a sweetening agent and certainpreservatives, dyes and colorings and flavors.

The compounds of the present invention may also be mixed with otheractive materials that do not impair the desired action, or withmaterials that supplement the desired action, such as antacids, H2blockers, and diuretics. For example, if a compound is used for treatingasthma or hypertension, it may be used with other bronchodilators andantihypertensive agents, respectively.

Examples of pharmaceutically acceptable carriers that may be included intablets comprising compounds of the present invention include, but arenot limited to binders, lubricants, diluents, disintegrating agents,coloring agents, flavoring agents, and wetting agents. Enteric-coatedtablets, because of the enteric-coating, resist the action of stomachacid and dissolve or disintegrate in the neutral or alkaline intestines.Sugar-coated tablets may be compressed tablets to which different layersof pharmaceutically acceptable substances are applied. Film-coatedtablets may be compressed tablets that have been coated with polymers orother suitable coating. Multiple compressed tablets may be compressedtablets made by more than one compression cycle utilizing thepharmaceutically acceptable substances previously mentioned. Coloringagents may also be used in tablets. Flavoring and sweetening agents maybe used in tablets, and are especially useful in the formation ofchewable tablets and lozenges.

Examples of liquid oral dosage forms that may be used include, but arenot limited to, aqueous solutions, emulsions, suspensions, solutionsand/or suspensions reconstituted from non-effervescent granules andeffervescent preparations reconstituted from effervescent granules.

Examples of aqueous solutions that may be used include, but are notlimited to, elixirs and syrups. As used herein, elixirs refer to clear,sweetened, hydroalcoholic preparations. Examples of pharmaceuticallyacceptable carriers that may be used in elixirs include, but are notlimited to solvents. Particular examples of solvents that may be usedinclude glycerin, sorbitol, ethyl alcohol and syrup. As used herein,syrups refer to concentrated aqueous solutions of a sugar, for example,sucrose. Syrups may optionally further comprise a preservative.

Emulsions refer to two-phase systems in which one liquid is dispersed inthe form of small globules throughout another liquid. Emulsions mayoptionally be oil-in-water or water-in-oil emulsions. Examples ofpharmaceutically acceptable carriers that may be used in emulsionsinclude, but are not limited to non-aqueous liquids, emulsifying agentsand preservatives.

Examples of pharmaceutically acceptable substances that may be used innon-effervescent granules, to be reconstituted into a liquid oral dosageform, include diluents, sweeteners and wetting agents.

Examples of pharmaceutically acceptable substances that may be used ineffervescent granules, to be reconstituted into a liquid oral dosageform, include organic acids and a source of carbon dioxide.

Coloring and flavoring agents may optionally be used in all of the abovedosage forms.

Particular examples of preservatives that may be used include glycerin,methyl and propylparaben, benzoic add, sodium benzoate and alcohol.

Particular examples of non-aqueous liquids that may be used in emulsionsinclude mineral oil and cottonseed oil.

Particular examples of emulsifying agents that may be used includegelatin, acacia, tragacanth, bentonite, and surfactants such aspolyoxyethylene sorbitan monooleate.

Particular examples of suspending agents that may be used include sodiumcarboxymethylcellulose, pectin, tragacanth, Veegum and acacia. Diluentsinclude lactose and sucrose. Sweetening agents include sucrose, syrups,glycerin and artificial sweetening agents such as sodium cyclamate andsaccharin.

Particular examples of wetting agents that may be used include propyleneglycol monostearate, sorbitan monooleate, diethylene glycol monolaurate,and polyoxyethylene lauryl ether.

Particular examples of organic acids that may be used include citric andtartaric acid.

Sources of carbon dioxide that may be used in effervescent compositionsinclude sodium bicarbonate and sodium carbonate. Coloring agents includeany of the approved certified water soluble FD and C dyes, and mixturesthereof.

Particular examples of flavoring agents that may be used include naturalflavors extracted from plants such fruits, and synthetic blends ofcompounds that produce a pleasant taste sensation.

For a solid dosage form, the solution or suspension, in for examplepropylene carbonate, vegetable oils or triglycerides, is preferablyencapsulated in a gelatin capsule. Such solutions, and the preparationand encapsulation thereof, are disclosed in U.S. Pat. Nos. 4,328,245;4,409,239; and 4,410,545. For a liquid dosage form, the solution, e.g.,for example, in a polyethylene glycol, may be diluted with a sufficientquantity of a pharmaceutically acceptable liquid carrier, e.g., water,to be easily measured for administration.

Alternatively, liquid or semi-solid oral formulations may be prepared bydissolving or dispersing the active compound or salt in vegetable oils,glycols, triglycerides, propylene glycol esters (e.g., propylenecarbonate) and other such carriers, and encapsulating these solutions orsuspensions in hard or soft gelatin capsule shells. Other usefulformulations include those set forth in U.S. Pat. Nos. Re 28,819 and4,358,603.

Injectables, Solutions, and Emulsions

The present invention is also directed to compositions designed toadminister the compounds of the present invention by parenteraladministration, generally characterized by subcutaneous, intramuscularor intravenous injection. Injectables may be prepared in anyconventional form, for example as liquid solutions or suspensions, solidforms suitable for solution or suspension in liquid prior to injection,or as emulsions.

Examples of excipients that may be used in conjunction with injectablesaccording to the present invention include, but are not limited towater, saline, dextrose, glycerol or ethanol. The injectablecompositions may also optionally comprise minor amounts of non-toxicauxiliary substances such as wetting or emulsifying agents, pH bufferingagents, stabilizers, solubility enhancers, and other such agents, suchas for example, sodium acetate, sorbitan monolaurate, triethanolamineoleate and cyclodextrins. Implantation of a slow-release orsustained-release system, such that a constant level of dosage ismaintained (see, e.g., U.S. Pat. No. 3,710,795) is also contemplatedherein. The percentage of active compound contained in such parenteralcompositions is highly dependent on the specific nature thereof, as wellas the activity of the compound and the needs of the subject.

Parenteral administration of the formulations includes intravenous,subcutaneous and intramuscular administrations. Preparations forparenteral administration include sterile solutions ready for injection,sterile dry soluble products, such as the lyophilized powders describedherein, ready to be combined with a solvent just prior to use, includinghypodermic tablets, sterile suspensions ready for injection, sterile dryinsoluble products ready to be combined with a vehicle just prior to useand sterile emulsions. The solutions may be either aqueous ornonaqueous.

When administered intravenously, examples of suitable carriers include,but are not limited to physiological saline or phosphate buffered saline(PBS), and solutions containing thickening and solubilizing agents, suchas glucose, polyethylene glycol, and polypropylene glycol and mixturesthereof.

Examples of pharmaceutically acceptable carriers that may optionally beused in parenteral preparations include, but are not limited to aqueousvehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents,buffers, antioxidants, local anesthetics, suspending and dispersingagents, emulsifying agents, sequestering or chelating agents and otherpharmaceutically acceptable substances.

Examples of aqueous vehicles that may optionally be used include SodiumChloride Injection, Ringers Injection, Isotonic Dextrose Injection,Sterile Water Injection, Dextrose and Lactated Ringers Injection.

Examples of nonaqueous parenteral vehicles that may optionally be usedinclude fixed oils of vegetable origin, cottonseed oil, corn oil, sesameoil and peanut oil.

Antimicrobial agents in bacteriostatic or fungistatic concentrations maybe added to parenteral preparations, particularly when the preparationsare packaged in multiple-dose containers and thus designed to be storedand multiple aliquots to be removed. Examples of antimicrobial agentsthat may be used include phenols or cresols, mercurials, benzyl alcohol,chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters,thimerosal, benzalkonium chloride and benzethonium chloride.

Examples of isotonic agents that may be used include sodium chloride anddextrose. Examples of buffers that may be used include phosphate andcitrate. Examples of antioxidants that may be used include sodiumbisulfate. Examples of local anesthetics that may be used includeprocaine hydrochloride. Examples of suspending and dispersing agentsthat may be used include sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Examples of emulsifying agentsthat may be used include Polysorbate 80 (TWEEN 80). A sequestering orchelating agent of metal ions includes EDTA.

Pharmaceutical carriers may also optionally include ethyl alcohol,polyethylene glycol and propylene glycol for water miscible vehicles andsodium hydroxide, hydrochloric acid, citric acid or lactic acid for pHadjustment.

The concentration of an inhibitor in the parenteral formulation may beadjusted so that an injection administers a pharmaceutically effectiveamount sufficient to produce the desired pharmacological effect. Theexact concentration of an inhibitor and/or dosage to be used willultimately depend on the age, weight and condition of the patient oranimal as is known in the art.

Unit-dose parenteral preparations may be packaged in an ampoule, a vialor a syringe with a needle. All preparations for parenteraladministration should be sterile, as is known and practiced in the art.

Injectables may be designed for local and systemic administration.Typically a therapeutically effective dosage is formulated to contain aconcentration of at least about 0.1% w/w up to about 90% w/w or more,preferably more than 1% w/w of the MEK inhibitor to the treatedtissue(s). The inhibitor may be administered at once, or may be dividedinto a number of smaller doses to be administered at intervals of time.It is understood that the precise dosage and duration of treatment willbe a function of the location of where the composition is parenterallyadministered, the carrier and other variables that may be determinedempirically using known testing protocols or by extrapolation from invivo or in vitro test data. It is to be noted that concentrations anddosage values may also vary with the age of the individual treated. Itis to be further understood that for any particular subject, specificdosage regimens may need to be adjusted over time according to theindividual need and the professional judgment of the personadministering or supervising the administration of the formulations.Hence, the concentration ranges set forth herein are intended to beexemplary and are not intended to limit the scope or practice of theclaimed formulations.

The MEK inhibitor may optionally be suspended in micronized or othersuitable form or may be derivatized to produce a more soluble activeproduct or to produce a prodrug. The form of the resulting mixturedepends upon a number of factors, including the intended mode ofadministration and the solubility of the compound in the selectedcarrier or vehicle. The effective concentration is sufficient forameliorating the symptoms of the disease state and may be empiricallydetermined.

Lyophilized Powders

The compounds of the present invention may also be prepared aslyophilized powders, which can be reconstituted for administration assolutions, emulsions and other mixtures. The lyophilized powders mayalso be formulated as solids or gels.

Sterile, lyophilized powder may be prepared by dissolving the compoundin a sodium phosphate buffer solution containing dextrose or othersuitable excipient. Subsequent sterile filtration of the solutionfollowed by lyophilization under standard conditions known to those ofskill in the art provides the desired formulation. Briefly, thelyophilized powder may optionally be prepared by dissolving dextrose,sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose orother suitable agent, about 1-20%, preferably about 5 to 15%, in asuitable buffer, such as citrate, sodium or potassium phosphate or othersuch buffer known to those of skill in the art at, typically, aboutneutral pH. Then, a MEK inhibitor is added to the resulting mixture,preferably above room temperature, more preferably at about 30-35° C.,and stirred until it dissolves. The resulting mixture is diluted byadding more buffer to a desired concentration. The resulting mixture issterile filtered or treated to remove particulates and to insuresterility, and apportioned into vials for lyophilization. Each vial maycontain a single dosage or multiple dosages of the inhibitor.

Topical Administration

The compounds of the present invention may also be administered astopical mixtures. Topical mixtures may be used for local and systemicadministration. The resulting mixture may be a solution, suspension,emulsions or the like and are formulated as creams, gels, ointments,emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes,foams, aerosols, irrigations, sprays, suppositories, bandages, dermalpatches or any other formulations suitable for topical administration.

The MEK inhibitors may be formulated as aerosols for topicalapplication, such as by inhalation (see, U.S. Pat. Nos. 4,044,126,4,414,209, and 4,364,923, which describe aerosols for delivery of asteroid useful for treatment of inflammatory diseases, particularlyasthma). These formulations for administration to the respiratory tractcan be in the form of an aerosol or solution for a nebulizer, or as amicrofine powder for insufflation, alone or in combination with an inertcarrier such as lactose. In such a case, the particles of theformulation will typically have diameters of less than 50 microns,preferably less than 10 microns.

The inhibitors may also be formulated for local or topical application,such as for topical application to the skin and mucous membranes, suchas in the eye, in the form of gels, creams, and lotions and forapplication to the eye or for intracisternal or intraspinal application.Topical administration is contemplated for transdermal delivery and alsofor administration to the eyes or mucosa, or for inhalation therapies.Nasal solutions of the MEK inhibitor alone or in combination with otherpharmaceutically acceptable excipients can also be administered.

Formulations for Other Routes of Administration

Depending upon the disease state being treated, other routes ofadministration, such as topical application, transdermal patches, andrectal administration, may also be used. For example, pharmaceuticaldosage forms for rectal administration are rectal suppositories,capsules and tablets for systemic effect. Rectal suppositories are usedherein mean solid bodies for insertion into the rectum that melt orsoften at body temperature releasing one or more pharmacologically ortherapeutically active ingredients. Pharmaceutically acceptablesubstances utilized in rectal suppositories are bases or vehicles andagents to raise the melting point. Examples of bases include cocoabutter (theobroma oil), glycerin-gelatin, carbowax, (polyoxyethyleneglycol) and appropriate mixtures of mono-, di- and triglycerides offatty acids. Combinations of the various bases may be used. Agents toraise the melting point of suppositories include spermaceti and wax.Rectal suppositories may be prepared either by the compressed method orby molding. The typical weight of a rectal suppository is about 2 to 3gm. Tablets and capsules for rectal administration may be manufacturedusing the same pharmaceutically acceptable substance and by the samemethods as for formulations for oral administration.

Examples of Formulations

The following are particular examples of oral, intravenous and tabletformulations that may optionally be used with compounds of the presentinvention. It is noted that these formulations may be varied dependingon the particular compound being used and the indication for which theformulation is going to be used.

ORAL FORMULATION Compound of the Present Invention 10-100 mg Citric AcidMonohydrate 105 mg Sodium Hydroxide 18 mg Flavoring Water q.s. to 100 mL

INTRAVENOUS FORMULATION Compound of the Present Invention 0.1-10 mgDextrose Monohydrate q.s. to make isotonic Citric Acid Monohydrate 1.05mg Sodium Hydroxide 0.18 mg Water for Injection q.s. to 1.0 mL

TABLET FORMULATION Compound of the Present Invention 1% MicrocrystallineCellulose 73% Stearic Acid 25% Colloidal Silica 1%Kits Comprising MEK Inhibitors

The invention is also directed to kits and other articles of manufacturefor treating diseases associated with MEK. It is noted that diseases areintended to cover all conditions for which the MEK possess activity thatcontributes to the pathology and/or symptomology of the condition.

In one embodiment, a kit is provided that comprises a compositioncomprising at least one inhibitor of the present invention incombination with instructions. The instructions may indicate the diseasestate for which the composition is to be administered, storageinformation, dosing information and/or instructions regarding how toadminister the composition. The kit may also comprise packagingmaterials. The packaging material may comprise a container for housingthe composition. The kit may also optionally comprise additionalcomponents, such as syringes for administration of the composition. Thekit may comprise the composition in single or multiple dose forms.

In another embodiment, an article of manufacture is provided thatcomprises a composition comprising at least one inhibitor of the presentinvention in combination with packaging materials. The packagingmaterial may comprise a container for housing the composition. Thecontainer may optionally comprise a label indicating the disease statefor which the composition is to be administered, storage information,dosing information and/or instructions regarding how to administer thecomposition. The kit may also optionally comprise additional components,such as syringes for administration of the composition. The kit maycomprise the composition in single or multiple dose forms.

It is noted that the packaging material used in kits and articles ofmanufacture according to the present invention may form a plurality ofdivided containers such as a divided bottle or a divided foil packet.The container can be in any conventional shape or form as known in theart which is made of a pharmaceutically acceptable material, for examplea paper or cardboard box, a glass or plastic bottle or jar, are-sealable bag (for example, to hold a “refill” of tablets forplacement into a different container), or a blister pack with individualdoses for pressing out of the pack according to a therapeutic schedule.The container that is employed will depend on the exact dosage forminvolved, for example a conventional cardboard box would not generallybe used to hold a liquid suspension. It is feasible that more than onecontainer can be used together in a single package to market a singledosage form. For example, tablets may be contained in a bottle that isin turn contained within a box. Typically the kit includes directionsfor the administration of the separate components. The kit form isparticularly advantageous when the separate components are preferablyadministered in different dosage forms (e.g., oral, topical, transdermaland parenteral), are administered at different dosage intervals, or whentitration of the individual components of the combination is desired bythe prescribing physician.

One particular example of a kit according to the present invention is aso-called blister pack. Blister packs are well known in the packagingindustry and are being widely used for the packaging of pharmaceuticalunit dosage forms (tablets, capsules, and the like). Blister packsgenerally consist of a sheet of relatively stiff material covered with afoil of a preferably transparent plastic material. During the packagingprocess recesses are formed in the plastic foil. The recesses have thesize and shape of individual tablets or capsules to be packed or mayhave the size and shape to accommodate multiple tablets and/or capsulesto be packed. Next, the tablets or capsules are placed in the recessesaccordingly and the sheet of relatively stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are individually sealed or collectively sealed, as desired, inthe recesses between the plastic foil and the sheet. Preferably thestrength of the sheet is such that the tablets or capsules can beremoved from the blister pack by manually applying pressure on therecesses whereby an opening is formed in the sheet at the place of therecess. The tablet or capsule can then be removed via said opening.

Another specific embodiment of a kit is a dispenser designed to dispensethe daily doses one at a time in the order of their intended use.Preferably, the dispenser is equipped with a memory-aid, so as tofurther facilitate compliance with the regimen. An example of such amemory-aid is a mechanical counter that indicates the number of dailydoses that has been dispensed. Another example of such a memory-aid is abattery-powered micro-chip memory coupled with a liquid crystal readout,or audible reminder signal which, for example, reads out the date thatthe last daily dose has been taken and/or reminds one when the next doseis to be taken.

Dosage, Host and Safety

The compounds of the present invention are stable and can be usedsafely. In particular, the compounds of the present invention are usefulas MEK inhibitors for a variety of subjects (e.g., humans, non-humanmammals and non-mammals). The optimal dose may vary depending upon suchconditions as, for example, the type of subject, the body weight of thesubject, the route of administration, and specific properties of theparticular compound being used. In general, the daily dose for oraladministration to an adult (body weight of about 60 kg) is about 1 to1000 mg, about 3 to 300 mg, or about 10 to 200 mg. It will beappreciated that the daily dose can be given in a single administrationor in multiple (e.g., 2 or 3) portions a day.

Combination Therapies

A wide variety therapeutic agents may have a therapeutic additive orsynergistic effect with MEK inhibitors according to the presentinvention. Such therapeutic agents may additively or synergisticallycombine with the MEK inhibitors to inhibit undesirable cell growth, suchas inappropriate cell growth resulting in undesirable benign conditionsor tumor growth.

In one embodiment, a method is provided for treating a cellproliferative disease state comprising treating cells with a compoundaccording to the present invention in combination with ananti-proliferative agent, wherein the cells are treated with thecompound according to the present invention before, at the same time,and/or after the cells are treated with the anti-proliferative agent,referred to herein as combination therapy. It is noted that treatment ofone agent before another is referred to herein as sequential therapy,even if the agents are also administered together. It is noted thatcombination therapy is intended to cover when agents are administeredbefore or after each other (sequential therapy) as well as when theagents are administered at the same time.

Examples of therapeutic agents that may be used in combination with MEKinhibitors include, but are not limited to, anticancer agents,alkylating agents, antibiotic agents, antimetabolic agents, hormonalagents, plant-derived agents, and biologic agents.

Alkylating agents are polyfunctional compounds that have the ability tosubstitute alkyl groups for hydrogen ions. Examples of alkylating agentsinclude, but are not limited to, bischloroethylamines (nitrogenmustards, e.g. chlorambucil, cyclophosphamide, ifosfamide,mechlorethamine, melphalan, uracil mustard), aziridines (e.g. thiotepa),alkyl alkone sulfonates (e.g. busulfan), nitrosoureas (e.g. carmustine,lomustine, streptozocin), nonclassic alkylating agents (altretamine,dacarbazine, and procarbazine), platinum compounds (carboplastin andcisplatin). These compounds react with phosphate, amino, hydroxyl,sulfihydryl, carboxyl, and imidazole groups. Under physiologicalconditions, these drugs ionize and produce positively charged ion thatattach to susceptible nucleic acids and proteins, leading to cell cyclearrest and/or cell death. Combination therapy including a MEK inhibitorand an alkylating agent may have therapeutic synergistic effects oncancer and reduce sides affects associated with these chemotherapeuticagents.

Antibiotic agents are a group of drugs that produced in a manner similarto antibiotics as a modification of natural products. Examples ofantibiotic agents include, but are not limited to, anthracyclines (e.g.doxorubicin, daunorubicin, epirubicin, idarubicin and anthracenedione),mitomycin C, bleomycin, dactinomycin, plicatomycin. These antibioticagents interfere with cell growth by targeting different cellularcomponents. For example, anthracyclines are generally believed tointerfere with the action of DNA topoisomerase II in the regions oftranscriptionally active DNA, which leads to DNA strand scissions.Bleomycin is generally believed to chelate iron and forms an activatedcomplex, which then binds to bases of DNA, causing strand scissions andcell death. Combination therapy including a MEK inhibitor and anantibiotic agent may have therapeutic synergistic effects on cancer andreduce sides affects associated with these chemotherapeutic agents.

Antimetabolic agents are a group of drugs that interfere with metabolicprocesses vital to the physiology and proliferation of cancer cells.Actively proliferating cancer cells require continuous synthesis oflarge quantities of nucleic acids, proteins, lipids, and other vitalcellular constituents. Many of the antimetabolites inhibit the synthesisof purine or pyrimidine nucleosides or inhibit the enzymes of DNAreplication. Some antimetabolites also interfere with the synthesis ofribonucleosides and RNA and/or amino acid metabolism and proteinsynthesis as well. By interfering with the synthesis of vital cellularconstituents, antimetabolites can delay or arrest the growth of cancercells. Examples of antimetabolic agents include, but are not limited to,fluorouracil (5-FU), floxuridine (5-FUdR), methotrexate, leucovorin,hydroxyurea, thioguanine (6-TG), mercaptopurine (6-MP), cytarabine,pentostatin, fludarabine phosphate, cladribine (2-CDA), asparaginase,and gemcitabine. Combination therapy including a MEK inhibitor and aantimetabolic agent may have therapeutic synergistic effects on cancerand reduce sides affects associated with these chemotherapeutic agents.

Hormonal agents are a group of drug that regulate the growth anddevelopment of their target organs. Most of the hormonal agents are sexsteroids and their derivatives and analogs thereof, such as estrogens,androgens, and progestins. These hormonal agents may serve asantagonists of receptors for the sex steroids to down regulate receptorexpression and transcription of vital genes. Examples of such hormonalagents are synthetic estrogens (e.g. diethylstibestrol), antiestrogens(e.g. tamoxifen, toremifene, fluoxymesterol and raloxifene),antiandrogens (bicalutamide, nilutamide, and flutamide), aromataseinhibitors (e.g., aminoglutethimide, anastrozole and tetrazole),ketoconazole, goserelin acetate, leuprolide, megestrol acetate, andmifepristone. Combination therapy including a MEK inhibitor and ahormonal agent may have therapeutic synergistic effects on cancer andreduce sides affects associated with these chemotherapeutic agents.

Plant-derived agents are a group of drugs that are derived from plantsor modified based on the molecular structure of the agents. Examples ofplant-derived agents include, but are not limited to, vinca alkaloids(e.g., vincristine, vinblastine, vindesine, vinzolidine andvinorelbine), podophyllotoxins (e.g., etoposide (VP-16), teniposide(VM-26)), and taxanes (e.g., paclitaxel and docetaxel). Theseplant-derived agents generally act as antimitotic agents that bind totubulin and inhibit mitosis. Podophyllotoxins such as etoposide arebelieved to interfere with DNA synthesis by interacting withtopoisomerase II, leading to DNA strand scission. Combination therapyincluding a MEK inhibitor and a plant-derived agent may have therapeuticsynergistic effects on cancer and reduce sides affects associated withthese chemotherapeutic agents.

Biologic agents are a group of biomolecules that elicit cancer/tumorregression when used alone or in combination with chemotherapy and/orradiotherapy. Examples of biologic agents include, but are not limitedto, immuno-modulating proteins such as cytokines, monoclonal antibodiesagainst tumor antigens, tumor suppressor genes, and cancer vaccines.Combination therapy including a MEK inhibitor and a biologic agent mayhave therapeutic synergistic effects on cancer, enhance the patient'simmune responses to tumorigenic signals, and reduce potential sidesaffects associated with this chemotherapeutic agent.

Cytokines possess profound immunomodulatory activity. Some cytokinessuch as interleukin-2 (IL-2, aldesleukin) and interferon havedemonstrated antitumor activity and have been approved for the treatmentof patients with metastatic renal cell carcinoma and metastaticmalignant melanoma. IL-2 is a T-cell growth factor that is central toT-cell-mediated immune responses. The selective antitumor effects ofIL-2 on some patients are believed to be the result of a cell-mediatedimmune response that discriminate between self and nonself. Examples ofinterleukins that may be used in conjunction with MEK inhibitor include,but are not limited to, interleukin 2 (IL-2), and interleukin 4 (IL-4),interleukin 12 (IL-12).

Interferon include more than 23 related subtypes with overlappingactivities, all of the IFN subtypes within the scope of the presentinvention. IFN has demonstrated activity against many solid andhematologic malignancies, the later appearing to be particularlysensitive.

Other cytokines that may be used in conjunction with a MEK inhibitorinclude those cytokines that exert profound effects on hematopoiesis andimmune functions. Examples of such cytokines include, but are notlimited to erythropoietin, granulocyte-CSF (filgrastin), andgranulocyte, macrophage-CSF (sargramostim). These cytokines may be usedin conjunction with a MEK inhibitor to reduce chemotherapy-inducedmyelopoietic toxicity.

Other immuno-modulating agents other than cytokines may also be used inconjunction with a MEK inhibitor to inhibit abnormal cell growth.Examples of such immuno-modulating agents include, but are not limitedto bacillus Calmette-Guerin, levamisole, and octreotide, a long-actingoctapeptide that mimics the effects of the naturally occurring hormonesomatostatin.

Monoclonal antibodies against tumor antigens are antibodies elicitedagainst antigens expressed by tumors, preferably tumor-specificantigens. For example, monoclonal antibody HERCEPTIN® (Trastruzumab) israised against human epidermal growth factor receptor2 (HER2) that isoverexpressed in some breast tumors including metastatic breast cancer.Overexpression of HER2 protein is associated with more aggressivedisease and poorer prognosis in the clinic. HERCEPTIN® is used as asingle agent for the treatment of patients with metastatic breast cancerwhose tumors over express the HER2 protein. Combination therapyincluding MEK inhibitor and HERCEPTIN® may have therapeutic synergisticeffects on tumors, especially on metastatic cancers.

Another example of monoclonal antibodies against tumor antigens isRITUXAN® (Rituximab) that is raised against CD20 on lymphoma cells andselectively deplete normal and malignant CD20⁺ pre-B and mature B cells.RITUXAN® is used as single agent for the treatment of patients withrelapsed or refractory low-grade or follicular, CD20+, B cellnon-Hodgkin's lymphoma. Combination therapy including MEK inhibitor andRITUXAN® may have therapeutic synergistic effects not only on lymphoma,but also on other forms or types of malignant tumors.

Tumor suppressor genes are genes that function to inhibit the cellgrowth and division cycles, thus preventing the development ofneoplasia. Mutations in tumor suppressor genes cause the cell to ignoreone or more of the components of the network of inhibitory signals,overcoming the cell cycle check points and resulting in a higher rate ofcontrolled cell growth-cancer. Examples of the tumor suppressor genesinclude, but are not limited to, DPC-4, NF-1, NF-2, RB, p53, WT1, BRCA1,and BRCA2.

DPC-4 is involved in pancreatic cancer and participates in a cytoplasmicpathway that inhibits cell division. NF-1 codes for a protein thatinhibits Ras, a cytoplasmic inhibitory protein. NF-1 is involved inneurofibroma and pheochromocytomas of the nervous system and myeloidleukemia. NF-2 encodes a nuclear protein that is involved in meningioma,schwanoma, and ependymoma of the nervous system. RB codes for the pRBprotein, a nuclear protein that is a major inhibitor of cell cycle. RBis involved in retinoblastoma as well as bone, bladder, small cell lungand breast cancer. P53 codes for p53 protein that regulates celldivision and can induce apoptosis. Mutation and/or inaction of p53 isfound in a wide ranges of cancers. WT1 is involved in Wilms tumor of thekidneys. BRCA1 is involved in breast and ovarian cancer, and BRCA2 isinvolved in breast cancer. The tumor suppressor gene can be transferredinto the tumor cells where it exerts its tumor suppressing functions.Combination therapy including a MEK inhibitor and a tumor suppressor mayhave therapeutic synergistic effects on patients suffering from variousforms of cancers.

Cancer vaccines are a group of agents that induce the body's specificimmune response to tumors. Most of cancer vaccines under research anddevelopment and clinical trials are tumor-associated antigens (TAAs).TAA are structures (i.e. proteins, enzymes or carbohydrates) which arepresent on tumor cells and relatively absent or diminished on normalcells. By virtue of being fairly unique to the tumor cell, TAAs providetargets for the immune system to recognize and cause their destruction.Example of TAAs include, but are not limited to gangliosides (GM2),prostate specific antigen (PSA), alpha-fetoprotein (AFP),carcinoembryonic antigen (CEA) (produced by colon cancers and otheradenocarcinomas, e.g. breast, lung, gastric, and pancreas cancer s),melanoma associated antigens (MART-1, gp100, MAGE 1,3 tyrosinase),papillomavirus E6 and E7 fragments, whole cells or portions/lysates ofantologous tumor cells and allogeneic tumor cells.

An adjuvant may be used to augment the immune response to TAAs. Examplesof adjuvants include, but are not limited to, bacillus Calmette-Guerin(BCG), endotoxin lipopolysaccharides, keyhole limpet hemocyanin (GKLH),interleukin-2 (IL-2), granulocyte-macrophage colony-stimulating factor(GM-CSF) and cytoxan, a chemotherapeutic agent which is believe toreduce tumor-induced suppression when given in low doses.

Further examples of therapeutic agents that may be used in combinationwith MEK inhibitors include, but are not limited to, Pl3/Akt signalinginhibitors. Examples of Pl3/Akt inhibitors that may be used incombination with MEK inhibitors include, but are not limited to, humanepidermal growth factor receptor (HER2) inhibitors. Examples of HER2inhibitors include, but are not limited to, Herceptin® (Trastruzumab)and Tykerb® (Lapatinib). Tykerb®, a small molecule that can beadministered orally, inhibits the tyrosine kinase components of ErbB1and ErbB2 receptors. Stimulation of ErbB1 and ErbB2 is associated withcell proliferation and with multiple processes involved in tumorprogression, invasion, and metastasis. Overexpression of these receptorshas been reported in a variety of human tumors and is associated withpoor prognosis and reduced overall survival.

Still further examples of therapeutic agents that may be used incombination with MEK inhibitors include, but are not limited to, histonedeacetylase (HDAC) inhibitors. Examples of HDAC inhibitors that may beused in combination with MEK inhibitors include, but are not limited to,suberoylanilide hydroxamic acid (SAHA).

EXAMPLES Preparation of MEK Inhibitors

Various methods may be developed for synthesizing compounds according tothe present invention. Representative methods for synthesizing thesecompounds are provided in the Examples. It is noted, however, that thecompounds of the present invention may also be synthesized by othersynthetic routes that others may devise.

It will be readily recognized that certain compounds according to thepresent invention have atoms with linkages to other atoms that confer aparticular stereochemistry to the compound (e.g., chiral centers). It isrecognized that synthesis of compounds according to the presentinvention may result in the creation of mixtures of differentstereoisomers (i.e., enantiomers and diastereomers). Unless a particularstereochemistry is specified, recitation of a compound is intended toencompass all of the different possible stereoisomers.

Various methods for separating mixtures of different stereoisomers areknown in the art. For example, a racemic mixture of a compound may bereacted with an optically active resolving agent to form a pair ofdiastereoisomeric compounds. The diastereomers may then be separated inorder to recover the optically pure enantiomers. Dissociable complexesmay also be used to resolve enantiomers (e.g., crystallinediastereoisomeric salts). Diastereomers typically have sufficientlydistinct physical properties (e.g., melting points, boiling points,solubilities, reactivity, etc.) and can be readily separated by takingadvantage of these dissimilarities. For example, diastereomers cantypically be separated by chromatography or by separation/resolutiontechniques based upon differences in solubility. A more detaileddescription of techniques that can be used to resolve stereoisomers ofcompounds from their racemic mixture can be found in Jean Jacques AndreCollet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, JohnWiley & Sons, Inc. (1981).

Compounds according to the present invention can also be prepared as apharmaceutically acceptable acid addition salt by reacting the free baseform of the compound with a pharmaceutically acceptable inorganic ororganic acid. Alternatively, a pharmaceutically acceptable base additionsalt of a compound can be prepared by reacting the free acid form of thecompound with a pharmaceutically acceptable inorganic or organic base.Inorganic and organic acids and bases suitable for the preparation ofthe pharmaceutically acceptable salts of compounds are set forth in thedefinitions section of this Application. Alternatively, the salt formsof the compounds can be prepared using salts of the starting materialsor intermediates.

The free acid or free base forms of the compounds can be prepared fromthe corresponding base addition salt or acid addition salt form. Forexample, a compound in an acid addition salt form can be converted tothe corresponding free base by treating with a suitable base (e.g.,ammonium hydroxide solution, sodium hydroxide, and the like). A compoundin a base addition salt form can be converted to the corresponding freeacid by treating with a suitable acid (e.g., hydrochloric acid, etc).

The N-oxides of compounds according to the present invention can beprepared by methods known to those of ordinary skill in the art. Forexample, N-oxides can be prepared by treating an unoxidized form of thecompound with an oxidizing agent (e.g., trifluoroperacetic acid,permaleic acid, perbenzoic acid, peracetic acid,meta-chloroperoxybenzoic acid, or the like) in a suitable inert organicsolvent (e.g., a halogenated hydrocarbon such as dichloromethane) atapproximately 0° C. Alternatively, the N-oxides of the compounds can beprepared from the N-oxide of an appropriate starting material.

Compounds in an unoxidized form can be prepared from N-oxides ofcompounds by treating with a reducing agent (e.g., sulfur, sulfurdioxide, triphenyl phosphine, lithium borohydride, sodium borohydride,phosphorus trichloride, tribromide, or the like) in an suitable inertorganic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, or thelike) at 0 to 80° C.

Prodrug derivatives of the compounds can be prepared by methods known tothose of ordinary skill in the art (e.g., for further details seeSaulnier et al. (1994), Bioorganic and Medicinal Chemistry Letters, Vol.4, p. 1985). For example, appropriate prodrugs can be prepared byreacting a non-derivatized compound with a suitable carbamylating agent(e.g., 1,1-acyloxyalkylcarbonochloridate, para-nitrophenyl carbonate, orthe like).

Protected derivatives of the compounds can be made by methods known tothose of ordinary skill in the art. A detailed description of thetechniques applicable to the creation of protecting groups and theirremoval can be found in T. W. Greene, Protecting Groups in OrganicSynthesis, 3^(rd) edition, John Wiley & Sons, Inc. 1999.

Compounds according to the present invention may be convenientlyprepared, or formed during the process of the invention, as solvates(e.g., hydrates). Hydrates of compounds of the present invention may beconveniently prepared by recrystallization from an aqueous/organicsolvent mixture, using organic solvents such as dioxin, tetrahydrofuranor methanol.

Compounds according to the present invention can also be prepared astheir individual stereoisomers by reacting a racemic mixture of thecompound with an optically active resolving agent to form a pair ofdiastereoisomeric compounds, separating the diastereomers and recoveringthe optically pure enantiomer. While resolution of enantiomers can becarried out using covalent diastereomeric derivatives of compounds,dissociable complexes are preferred (e.g., crystalline diastereoisomericsalts). Diastereomers have distinct physical properties (e.g., meltingpoints, boiling points, solubilities, reactivity, etc.) and can bereadily separated by taking advantage of these dissimilarities. Thediastereomers can be separated by chromatography or, preferably, byseparation/resolution techniques based upon differences in solubility.The optically pure enantiomer is then recovered, along with theresolving agent, by any practical means that would not result inracemization. A more detailed description of the techniques applicableto the resolution of stereoisomers of compounds from their racemicmixture can be found in Jean Jacques Andre Collet, Samuel H. Wilen,Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Standard single-letteror three-letter abbreviations are generally used to designate amino acidresidues, which are assumed to be in the L-configuration unlessotherwise noted. Unless otherwise noted, all starting materials wereobtained from commercial suppliers and used without furtherpurification. Specifically, the following abbreviations may be used inthe examples and throughout the specification:

μL (microliters) Ac (acetyl) atm (atmosphere) ATP (AdenosineTriphophatase) BOC (tert-butyloxycarbonyl) BOP(bis(2-oxo-3-oxazolidinyl)phosphinic chloride) BSA (Bovine SerumAlbumin) CBZ (benzyloxycarbonyl) CDI (1,1-carbonyldiimidazole) DCC(dicyclohexylcarbodiimide) DCE (dichloroethane) DCM (dichloromethane)DMAP (4-dimethylaminopyridine) DME (1,2-dimethoxyethane) DMF(N,N-dimethylformamide) DMPU (N,N′-dimethylpropyleneurea) DMSO(dimethylsulfoxide) EDCI (ethylcarbodiimide hydrochloride) EDTA(Ethylenediaminetetraacetic acid) Et (ethyl) Et₂O (diethyl ether) EtOAc(ethyl acetate) FMOC (9-fluorenylmethoxycarbonyl) g (grams) h (hours)HOAc or AcOH (acetic acid) HOBT (1-hydroxybenzotriazole) HOSu(N-hydroxysuccinimide) HPLC (high pressure liquid chromatography) Hz(Hertz) i.v. (intravenous) IBCF (isobutyl chloroformate) i-PrOH(isopropanol) L (liters) M (molar) mCPBA (meta-chloroperbenzoic acid) Me(methyl) MeOH (methanol) mg (milligrams) MHz (megahertz) min (minutes)mL (milliliters) mM (millimolar) mmol (millimoles) mol (moles) MOPS(Morpholinepropanesulfonic acid) mp (melting point) NaOAc (sodiumacetate) OMe (methoxy) psi (pounds per square inch) RP (reverse phase)RT (ambient temperature) SPA (Scintillation Proximity Assay) TBAF(tetra-n-butylammonium fluoride) TBS (t-butyldimethylsilyl) tBu(tert-butyl) TEA (triethylamine) TFA (trifluoroacetic acid) TFAA(trifluoroacetic anhydride) THF (tetrahydrofuran) TIPS(triisopropylsilyl) TLC (thin layer chromatography) TMS (trimethylsilyl)TMSE (2-(trimethylsilyl)ethyl) Tr (retention time)

All references to ether or Et₂O are to diethyl ether; and brine refersto a saturated aqueous solution of NaCl. Unless otherwise indicated, alltemperatures are expressed in ° C. (degrees Centigrade). All reactionsare conducted under an inert atmosphere at RT unless otherwise noted.

¹H NMR spectra were recorded on a Bruker Avance 400. Chemical shifts areexpressed in parts per million (ppm). Coupling constants are in units ofHertz (Hz). Splitting patterns describe apparent multiplicities and aredesignated as s (singlet), d (doublet), t (triplet), q (quartet), m(multiplet), br (broad).

Low-resolution mass spectra (MS) and compound purity data were acquiredon a Waters ZQ LC/MS single quadrupole system equipped with electrosprayionization (ESI) source, UV detector (220 and 254 nm), and evaporativelight scattering detector (ELSD). Thin-layer chromatography wasperformed on 0.25 mm E. Merck silica gel plates (60F-254), visualizedwith UV light, 5% ethanolic phosphomolybdic acid, Ninhydrin orp-anisaldehyde solution. Flash column chromatography was performed onsilica gel (230-400 mesh, Merck).

The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as the AldrichChemical Company (Milwaukee, Wis.), Bachem (Torrance, Calif.), Sigma(St. Louis, Mo.), or may be prepared by methods well known to a personof ordinary skill in the art, following procedures described in suchstandard references as Fieser and Fieser's Reagents for OrganicSynthesis, vols. 1-17, John Wiley and Sons, New York, N.Y., 1991; Rodd'sChemistry of Carbon Compounds, vols. 1-5 and supps., Elsevier SciencePublishers, 1989; Organic Reactions, vols. 1-40, John Wiley and Sons,New York, N.Y., 1991; March J.: Advanced Organic Chemistry, 4th ed.,John Wiley and Sons, New York, N.Y.; and Larock: Comprehensive OrganicTransformations, VCH Publishers, New York, 1989.

The entire disclosures of all documents cited throughout thisapplication are incorporated herein by reference.

Synthetic Schemes for Compounds of the Present Invention

Compounds according to the present invention may be synthesizedaccording to the reaction schemes shown below. Other reaction schemescould be readily devised by those skilled in the art. It should also beappreciated that a variety of different solvents, temperatures and otherreaction conditions can be varied to optimize the yields of thereactions.

In the reactions described hereinafter it may be necessary to protectreactive functional groups, for example hydroxy, amino, imino, thio orcarboxy groups, where these are desired in the final product, to avoidtheir unwanted participation in the reactions. Conventional protectinggroups may be used in accordance with standard practice, for examplessee T. W. Greene and P. G. M. Wuts in “Protective Groups in OrganicChemistry” John Wiley and Sons, 1991.

A general synthetic route for producing compounds of the presentinvention is shown in Scheme 1. Compound C is cyclized (e.g., in amicrowave reaction) with compound D to produce compound E. Reaction ofcompound E with compound F, where X is halo (e.g., Cl, Br or I) and—OR_(b) is a leaving group (e.g., R_(b)=halo or tosyl), gives compoundG. A displacement reaction between compound G and compound H producescompound I. In particular embodiments, R₁ of compound F is a substitutedor unsubstituted aryl (e.g., phenyl).

Compounds of the present invention can also be prepared as shown inScheme 2. Desulfurization of compound J with Raney Nickel providescompound C(X₅═CH; R₄═H), which is then cyclized (e.g., in a microwavereaction) with compound D to produce compound E (X₁═CH; X₂═CO; X₅═CH;R₄═H). Reaction of compound E with compound F gives compound G (X₁═CH;X₂═CO; X₅═CH; R₄═H). A displacement reaction of compound G with compoundH produces compound I (X₁═CH; X₂═CO; X₅═CH; R₄═H).

A general synthetic route for producing compounds of the presentinvention is shown in Scheme 3. Compound C is cyclized (e.g., in amicrowave reaction or heating conditions) with compound D to producecompound L (R₆=alkyl). Reaction of compound L with PDX₃, (e.g., X is Clor Br) gives compound M. A displacement reaction between compound M andcompound H produces compound N. In particular embodiments, R₁ ofcompound N is a substituted or unsubstituted aryl.

When R₃′ is a protecting group (e.g., PMB), compound N can bede-protected by removal of R₃′ to give compound O, which upon heatingwith 1-chloro-2,4-dinitrobenzene in the presence of a base, such asCs₂CO₃, K₂CO₃ or the like, gives compound P. Compound P can then betreated with primary amine Q under heating conditions to providecompound R.

Chiral components can be separated and purified using any of a varietyof techniques known to those skilled in the art. For example, chiralcomponents can be purified using supercritical fluid chromatography(SFC). In one particular variation, chiral analytical SFC/MS analysesare conducted using a Berger analytical SFC system (AutoChem, Newark,Del.) which consists of a Berger SFC dual pump fluid control module witha Berger FCM 1100/1200 supercritical fluid pump and FCM 1200 modifierfluid pump, a Berger TCM 2000 oven, and an Alcott 718 autosampler. Theintegrated system can be controlled by BI-SFC Chemstation softwareversion 3.4. Detection can be accomplished with a Watrers ZQ 2000detector operated in positive mode with an ESI interface and a scanrange from 200-800 Da with 0.5 second per scan. Chromatographicseparations can be performed on a ChiralPak AD-H, ChiralPak AS-H,ChiralCel OD-H, or ChiralCel OJ-H column (5μ, 4.6×250 mm; ChiralTechnologies, Inc. West Chester, Pa.) with 10 to 40% methanol as themodifier and with or without ammonium acetate (10 mM). Any of a varietyof flow rates can be utilized including, for example, 1.5 or 3.5 mL/minwith an inlet pressure set at 100 bar. Additionally, a variety of sampleinjection conditions can be used including, for example, sampleinjections of either 5 or 10 μL in methanol at 0.1 mg/mL inconcentration.

In another variation, preparative chiral separations are performed usinga Berger MultiGram II SFC purification system. For example, samples canbe loaded onto a ChiralPak AD column (21×250 mm, 10μ). In particularvariations, the flow rate for separation can be 70 mL/min, the injectionvolume up to 2 mL, and the inlet pressure set at 130 bar. Stackedinjections can be applied to increase the efficiency.

In each of the above reaction procedures or schemes, the varioussubstituents may be selected from among the various substituentsotherwise taught herein.

Descriptions of the syntheses of particular compounds according to thepresent invention based on the above reaction scheme are set forthherein.

Examples of MEK Inhibitors

The present invention is further exemplified, but not limited by, thefollowing examples that describe the synthesis of particular compoundsaccording to the invention.

Example 15-(2-fluoro-4-iodophenylamino)-3,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

Referring to scheme 1,3-methyl-6-(methylamino)-2-(methylthio)pyrimidin-4(3H)-one (compound 1A;650 mg, 0.35 mmol, 1 eq) was suspended in methanol (5 ml). A largeexcess of Raney Nickel slurried in water was added (approx 5 ml) and themixture stirred at room temperature overnight to yield compound 1B. Theproduct was confirmed by LC-MS. The mixture was filtered and the solidwashed several times with methanol. The filtrate was then removed invacuo and the residue was purified by flash chromatography with 1:10MeOH:DCM to leave 3-methyl-6-(methylamino)pyrimidin-4(3H)-one (compound1B) as a yellow/green solid (380 mg, 86%). ¹H NMR (400 MHz, MeOD) δ ppm2.78 (s, 3H) 3.35 (s, 3H) 5.22 (br. s., 1H) 8.10 (br. s., 1H); [M+H]calc'd for C₅H₇N₃O, 126. found, 126.

3-Methyl-6-(methylamino)pyrimidin-4(3H)-one (compound 1B; 400 mg, 2.88mmol, 1 eq), diethyl malonate (873 μl, 5.76 mmol, 2 eq) and phenyl ether(915 μl, 5.76 mmol, 2 eq) were dissolved in 1-methyl-2-pyrrolidinone (2ml, 20 mmol). The mixture was placed in a microwave reactor at 240° C.for 30 minutes to yield5-hydroxy-3,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (compound1C). The product was confirmed by LC-MS and isolated by HPLC to give 125mg (21%) of compound 1C. [M+H] calc'd for C₉H₉N₃O₃, 208. found, 208.

5-hydroxy-3,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (compound1C, 125 mg, 0.60 mmol, 1 eq), p-toluenesulfonyl chloride (138 mg, 0.72mmol, 1.2 eq) and triethylamine (126 μl, 0.90 mmol, 1.5 eq) weredissolved in acetonitrile (2 ml). The mixture was heated at reflux (oilbath at 110° C.) for 3 hours to yield3,8-dimethyl-4,7-dioxo-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidin-5-yl4-methylbenzenesulfonate (compound 1D). The product was confirm byLC-MS. Solvent was removed in vacuo and the crude product3,8-dimethyl-4,7-dioxo-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidin-5-yl4-methylbenzenesulfonate used in the following reaction.

3,8-dimethyl-4,7-dioxo-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidin-5-yl4-methylbenzenesulfonate (compound 1D, 80 mg of 60% pure material) and2-fluoro-4-iodoaniline (300 mg, large excess) were heated at 125° C. for2 hours to yield5-(2-fluoro-4-iodophenylamino)-3,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(Example 1). The product was confirmed by LC-MS and isolated by HPLC togive the title compound as a tan solid (17 mg). ¹H NMR (400 MHz, MeOD) δppm 3.57 (s, 3H) 3.64 (s, 3H) 5.76 (s, 1H) 7.30 (t, J=8.34 Hz, 1H) 7.61(dt, J=8.34, 1.01 Hz, 1H) 7.66 (dd, J=9.85, 1.77 Hz, 1H) 8.48 (s, 1H);[M+H] calc'd for C₁₅H₁₂FIN₄O₂, 427. found, 427.

Example 25-(2-fluoro-4-iodophenylamino)-3-(2-hydroxyethyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

A mixture of 6-(methylamino)pyrimidin-4(3H)-one (compound 1B, 0.5 g, 4mmol, 1 eq), 2-(2-bromoethoxy)tetrahydro-2H-pyran (compound 2B, 0.836 g,4 mmol, 1 eq) and K₂CO₃ (0.5 g, 3.62 mmol) in DMF (15 ml) was heated bymicrowave at 85° C. for 90 minutes. DMF was removed under vacuum and theresidue was purified by flash chromatography using 0-5% CH₃OH/CH₂Cl₂over 30 minutes. Compound 2C was obtained as a colorless sticky liquid(0.8 g, 57%). [M+H] calc'd for C₁₂H₁₉N₃O₃, 254. found, 254.

Compound 2C (0.8 g, 3.16 mmol, 1 eq) and diethylmalonate (compound 2D,1.01 g, 7.32 mmol, 2 eq) were mixed in diphenylether (2 ml) and a dropof NMP was added. The mixture was heated by microwave at 240° C. for 30minutes. Compound 2E (0.41 g, 40%) was isolated as a white solid byflash chromatography using 0-5% CH₃OH/CH₂Cl₂ over 30 minutes. [M+H]calc'd for C₁₅H₁₉N₃O₅, 322. found, 322.

Compound 2E (0.41 g, 1.28 mmol, 1 eq) and P-toluenesulfonyl chloride(0.267 g, 1.40 mmol, 1.1 eq) were dissolved in CH₃CN (5 ml).Triethylamine (0.2 ml) was added. The mixture was then heated at 120° C.for 30 minutes. CH₃CN was removed under vacuum and the crude product waspurified by flash chromatography using 0-5% CH₃OH/CH₂Cl₂ over 30 minutesto give compound 2F (250 mg, 41%) as a white solid. [M+H] calc'd forC₂₂H₂₅N₃O₇S, 476. found, 476.

Compound 2F (0.25 g, 0.53 mmol, 1 eq) and 2-fluoro-4-iodoaniline (0.125g, 0.53 mmol, 1 eq) were mixed in THF (2 ml). The solution was cooled to−78° C. and 1.8 M LDA (0.877 ml, 3 eq) was added. The mixture was keptat −78° C. for 30 minutes, and then stirred at room temperature for 2 h.The solvent was removed and the crude product was purified by flashchromatography using 0-5% CH₃OH/CH₂Cl₂ over 30 minutes. Compound 2G (60mg, 21%) was isolated as a white solid. [M+H] calc'd for C₂₁H₂₂FIN₄O₄,541. found, 541.

To a solution of compound 2G (60 mg, 0.11 mmol) in THF (3 ml) was added1N HCl (1 ml). The mixture was stirred at room temperature for 2 h.Example 2 (12.6 mg, 25%) was purified by preparative HPLC. ¹H NMR (400MHz, Chloroform-d₁) δ 8.17 (s, 1H) 7.52 (m, 2H) 7.25 (t, J=8.08 Hz, 1H)5.78 (s, 1H) 4.11 (t, J=5.04 Hz, 2H) 4.00 (t, J=5.04 Hz, 2H) 3.54 (s,3H). [M+H] calc'd for C₁₆H₁₄FIN₄O₃, 457. found, 457.

Example 3 Methyl2-(5-(2-fluoro-4-iodophenylamino)-8-methyl-4,7-dioxo-7,8-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)acetate

The title compound was synthesized using a procedure analogous to thatdescribed in connection with Example 2. ¹H NMR (400 MHz, Methanol-d₄) δ8.47 (s, 1H) 7.63 (m, 2H) 7.28 (t, J=8.32 Hz, 1H) 5.74 (s, 1H) 4.84 (s,3H) 3.79 (s, 3H) 3.66 (s, 3H). [M+H] calc'd for C₁₇H₁₄FIN₄O₄, 485.found, 485.

Example 45-(2-fluoro-4-iodophenylamino)-3,6,8-trimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

6-(Methylamino)pyrimidin-4(3H)-one (0.2 g, 1.6 mmol, 1 eq) and 2.0 Miodomethane (0.8 ml, 1.6 mmol, 1 eq), K₂CO₃ (0.1 g, 0.72 mmol) weremixed in DMF (5 ml). The reaction was heated by microwave at 85° C. for90 minutes. DMF was removed under vacuum and the residue was purified bypreparative HPLC. Compound 4B was obtained as colorless sticky liquid(0.22 g, 98%). [M+H] calc'd for C₆H₉N₃O, 140. found, 140.

Compound 4B (0.22 g, 1.58 mmol, 1 eq) and 2-methyl diethylmalonate(0.275 g, 1.58 mmol, 1 eq) were mixed in diphenylether (2 ml) and a dropof NMP was added. The mixture was heated at 240° C. for 30 minutes usingmicrowave. Preparative HPLC purification provided compound 4C (0.1 g,28.5%) as a white solid. [M+H] calc'd for C₁₀H₁₁N₃O₃, 222. found, 222.

Compound 4C (0.02 g, 0.09 mmol, 1 eq) and P-toluenesulfonyl chloride(18.9 mg, 0.1 mmol, 1.1 eq) were dissolved in CH₃CN (2 ml),Triethylamine (3 drops) was added. The mixture was heated at 120° C. for30 minutes. CH₃CN was removed under vacuum and the crude was purified bypreparative HPLC to give 4D (17 mg, 50%) as a white solid. [M+H] calc'dfor C₁₇H₁₇N₃O₅S, 376. found, 376.

Compound 4D (10 mg, 0.027 mmol, 1 eq) and 2-fluoro-4-iodoaniline (6.3mg, 0.027 mmol, and 1 eq) were mixed in THF (2 ml). The solution wascooled to −78° C. and 1.8 M LDA (0.04 ml, 3 eq) was added. The mixturewas kept at −78° C. for 30 minutes and then stirred at room temperaturefor 2 h. THF was removed and the crude was purified by preparative HPLCto give Example 4 (1.1 mg, 9.4%) as a white solid. ¹H NMR (400 MHz,Chloroform-d₁) δ 8.11 (s, 1H) 7.34 (m, 2H) 6.48 (t, J=8.56 Hz, 1H) 3.74(s, 1H) 3.58 (s, 3H) 1.78 (s, 1H). [M+H] calc'd for C₁₆H₁₄FIN₄O₂, 441.found, 441.

Example 5(S)-3-(2,3-Dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

3-Benzyl-6-(methylamino)pyrimidin-4(3H)-one (compound 5A)

6-(Methylamino)pyrimidin-4(3H)-one (compound 1B; 3 g, 24 mmol, 1 eq),benzyl bromide (5.7 mL, 48 mmol, 2 eq) and potassium carbonate (6.96 g,50.4 mmol, 2.1 eq) were stirred in ethanol (30 mL) at RT overnight. Thesolvent was removed in vacuo and the residue purified by silicachromatography to give 2.25 g of the title compound (43%). ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.64 (d, J=4.29 Hz, 3H) 4.92-5.01 (m, 2H) 6.96 (q,J=4.63 Hz, 1H) 7.22-7.30 (m, 3H) 7.30-7.37 (m, 2H) 8.24 (s, 1H). [M+H]calc'd for C₁₂H₁₃N₃O, 216. found, 216.

3-Benzyl-5-hydroxy-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(compound 5B)

3-Benzyl-6-(methylamino)pyrimidin-4(3H)-one (compound 5A) (2 g, 9.3mmol, 1 eq) and diethyl malonate (2 mL, 14.5 mmol, 1.55 eq) were heatedin phenyl ether (3 mL, 19 mmol, 2 eq) at 240° C. in a microwave reactorfor 6 hours. Upon cooling a precipitate formed which was filtered andwashed with ether to give 1.5 g of the title compound as a tan solid(57%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.51 (s, 3H) 5.20 (s, 2H) 5.72(s, 1H) 7.31 (br. s., 1H) 7.38 (d, J=3.03 Hz, 4H) 8.93 (s, 1H) 11.61 (s,1H). [M+H] calc'd for C₁₅H₁₃N₃O₃, 284. found, 284.

3-Benzyl-5-chloro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(compound 5C)

3-Benzyl-5-hydroxy-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (1.1g, 3.88 mmol) was dissolved in excess POCl₃ (5 mL) and subjected tomicrowave irradiation at 70° C. for 30 minutes. The POCl₃ was removed invacuo and the residue dissolved in DCM then quickly washed withsaturated sodium bicarbonate solution until neutral pH was observed. Theorganic layer was dried over MgSO₄ and evaporated to dryness to give 1.5g of the title compound as a reddish brown solid (94%). [M+H] calc'd forC₁₅H₁₂ClN₃O, 302. found, 302.

3-Benzyl-5-(2-fluoro-4-nitrophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(compound 5D)

3-Benzyl-5-chloro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (950mg, 3.15 mmol, 1 eq), 2-fluoro-4-nitroaniline (540 mg, 3.46 mmol, 1.1eq), tris(dibenzylideneacetone)dipalladium(0) (58 mg, 0.06 mmol, 0.02eq), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (36 mg, 0.06 mmol,0.02 eq) and sodium tert-butoxide (453 mg, 4.7 mmol, 1.5 eq) were mixedin degassed anhydrous dioxane (7 mL) and subjected to microwaveirradiation at 100° C. for 30 minutes. Upon cooling a precipitate formedwhich was filtered and washed with cold dioxane (3 mL) to give 910 mg ofthe title compound (69%). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.55 (s, 3H)5.23 (s, 2H) 6.14 (s, 1H) 7.29-7.41 (m, 5H) 7.81-7.94 (m, 1H) 8.14 (d,J=10.86 Hz, 1H) 8.25 (d, J=11.12 Hz, 1H) 8.96 (s, 1H) 11.23 (s, 1H)[M+H] calc'd for C₂₁H₁₆FN₅O₄, 422. found, 422.

5-(4-Amino-2-fluorophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(compound 5E)

3-Benzyl-5-(2-fluoro-4-nitrophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(900 mg, 2.1 mmol), palladium hydroxide (20% on carbon, 500 mg) andammonium formate (500 mg, 7.9 3 mmol, 3.7 eq) were stirred in dioxane(10 mL) at 90° C. for 4 hours. The suspension was filtered and the solidrefluxed in DMF (20 mL) for 1 hour then filtered. This was repeated 3times. The filtrates were combined and evaporated to give 420 mg oftitle compound as a white solid (65%). ¹H NMR (400 MHz, MeOD) δ ppm 3.56(br. s., 3H) 5.38 (s, 1H) 6.51 (s, 1H) 6.54 (t, J=1.89 Hz, 1H) 7.07 (t,J=8.46 Hz, 1H) 8.17 (s, 1H) [M+H] calc'd for C₁₄H₁₂FN₅O₂, 302. found,302.

5-(4-Amino-2-fluorophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(compound 5F)

5-(4-Amino-2-fluorophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(580 mg, 1.9 mmol, 1 eq) was dissolved in a 1:1 mixture of acetic acidand water (10 mL) at 0° C. Sodium nitrite (133 mg, 1.9 mmol, 1 eq) inwater (200 μL) was added and the solution stirred for 20 minutes.Potassium iodide (1.59 g, 9.6 mmol, 5 eq) and iodine (20 mg, cat) inwater (4 mL) were added dropwise and the reaction allowed to warm to RTthen stirred overnight. The solution was diluted with water (100 mL) andthe extracted into 10% methanol/DCM. The organics were dried overmagnesium sulfate and evaporated and the resulting oil triturated withmethanol to give the title compound as a tan solid which was filtered in266 mg yield (29%). [M+H] calc'd for C₁₄H₁₀FIN₄O₂, 413. found, 413.

(S)-3-((2,2-Dimethyl-1,3-dioxolan-4-yl)methyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(compound 5G)

Sodium hydride (89 mg, 4.7 mmol, 5 eq) was stirred in anhydrous DMF (1mL) for 10 minutes.5-(2-Fluoro-4-iodophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(400 mg, 0.94 mmol, 1 eq) in anhydrous DMF (400 μL) was added and themixture stirred for 10 minutes.(R)-4-(Chloromethyl)-2,2-dimethyl-1,3-dioxolane (260 μl, 1.88 mmol, 2eq) was added and the mixture subjected to microwave irradiation at 150°C. for 35 minutes. The solvent was removed in vacuo and the residuepurified by HPLC. ¹H NMR (400 MHz, MeOD) δ ppm 1.37 (s, 3H) 1.47 (s, 3H)3.70 (s, 3H) 3.85 (dd, J=8.97, 5.68 Hz, 1H) 4.13 (dd, J=13.89, 7.07 Hz,1H) 4.20 (dd, J=8.72, 6.69 Hz, 1H) 4.38 (dd, J=13.89, 3.03 Hz, 1H)4.50-4.59 (m, 1H) 5.81 (s, 1H) 7.36 (t, J=8.21 Hz, 1H) 7.62-7.74 (m, 2H)8.49 (s, 1H). [M+H] calc'd for C₂₀H₂₀FIN₄O₄, 527. found, 527.

(S)-3-(2,3-Dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(Example 5)

Compound 5G (crude, −0.12 mmol) was dissolved in H₂O (1 mL) and THF (1mL). 1N HCl (1 mL) was added and the solution stirred at RT for 1 hour.After evaporation in vacuo the residue was purified by HPLC to give thetitle compound (22 mg, 37%, two steps). ¹H NMR (400 MHz, MeOD) δ ppm3.34 (s, 3H) 3.79 (dd, J=13.26, 8.72 Hz, 2H) 3.93-4.00 (m, 2H) 4.43 (dd,J=13.01, 2.91 Hz, 2H) 5.75 (s, 1H) 7.30 (t, J=8.34 Hz, 1H) 7.61 (dd,J=8.21, 1.89 Hz, 1H) 7.65 (dd, J=10.23, 1.89 Hz, 1H) 8.41 (s, 1H) [M+H]calc'd for C₁₇H₁₆FIN₄O₄, 487. found, 487.

Example 6(R)-3-(2,3-Dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

The title compound was prepared according to the procedure outlined inExample 5 synthesis, using starting material(S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane for the alkylation ofcompound 5F. ¹H NMR (400 MHz, MeOD) δ ppm 3.65 (s, 3H) 3.75-3.85 (m, 2H)3.90-4.02 (m, 2H) 4.43 (dd, J=13.14, 2.78 Hz, 2H) 5.75 (s, 1H) 7.30 (t,J=8.34 Hz, 1H) 7.61 (dd, J=8.59, 1.52 Hz, 1H) 7.65 (dd, J=9.85, 1.77 Hz,1H) 8.41 (s, 1H)[M+H] calc'd for C₁₇H₁₆FIN₄O₄, 487. found, 487.

Example 7(S)-6-Chloro-3-(2,3-dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

(S)-3-(2,3-Dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(compound 5G) (60 mg, 0.1 mmol, 1 eq) and N-chlorosuccinimide (15 mg,0.1 mmol, 1 eq) were stirred in DMF (2 mL) at RT for 1 hour. The productwas purified by HPLC to give 85 mg of a pale yellow oil. The oil wastaken up in H₂O (2 mL) and THF (2 mL). 1N HCl (1 mL) was added and thesolution stirred at RT for 2 hours. The solution was neutralized withtriethylamine and purified by HPLC to give 6 mg of the title compound.¹H NMR (400 MHz, MeOD) δ ppm 3.33 (s, 3H) 3.77 (dd, J=13.26, 8.72 Hz,2H) 3.92-4.00 (m, 2H) 4.45 (dd, J=13.01, 2.91 Hz, 2H) 7.26 (t, J=8.34Hz, 1H) 7.55 (dd, J=8.21, 1.89 Hz, 1H) 7.65 (dd, J=10.23, 1.89 Hz, 1H)8.41 (s, 1H) [M+H] calc'd for C₁₇H₁₅ClFIN₄O₄, 521. found, 521.

Example 8(R)-3-(2,3-Dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

3-(4-Methoxybenzyl)-6-(methylamino)pyrimidin-4(3H)-one (compound 8A)

6-(Methylamino)pyrimidin-4(3H)-one (100 g, 800 mmol, 1 eq),p-methoxybenzyl chloride (124.8 g, 800 mmol, 1 eq), potassium iodide(13.3 g, 80 mmol, 0.1 eq) and cesium carbonate (260 g, 800 mmol, 1 eq)were stirred at RT in anhydrous DMF (1 L) for 8 hours. The DMF wasremoved in vacuo and the residue stirred overnight in 20% methanol/DCM.The solid was removed by filtration and washed with 20% methanol/DCM.The solvent was removed in vacuo and the resulting residue taken up inDCM then washed with water. The organic layer was dried over magnesiumsulfate and evaporated to give 102 g of the title compound (59%). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 2.63 (d, J=4.29 Hz, 3H) 3.72 (s, 3H) 4.87 (s,2H) 6.88 (d, J=8.84 Hz, 2H) 7.25 (d, J=8.59 Hz, 2H) 8.22 (s, 1H). [M+H]calc'd for C₁₃H₁₅N₃O₂, 246. found, 246.

5-Hydroxy-3-(4-methoxybenzyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(compound 8B)

3-(4-Methoxybenzyl)-6-(methylamino)pyrimidin-4(3H)-one (14.8 g, 60.2mmol, 1 eq, compound 8A) and diethyl methylmalonate (61.6 mL, 361 mmol,6 eq) were mixed in phenyl ether (25 mL) and heated at 240° C. for 2days. The solution was allowed to RT and left standing overnight. Thetan precipitate which formed was collected and washed with ether to give15.2 g of the title compound as a tan solid (78%). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.89 (s, 3H) 3.55 (s, 3H) 3.74 (s, 3H) 5.14 (s, 2H) 6.93(d, J=8.59 Hz, 2H) 7.37 (d, J=8.59 Hz, 2H) 8.89 (s, 1H) 11.82 (s, 1H).%). [M+H] calc'd for C₁₇H₁₇N₃O₄, 328. found, 328.

5-Chloro-3-(4-methoxybenzyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(compound 8C)

5-Hydroxy-3-(4-methoxybenzyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(10 g, 30.6 mmol, compound 8B) was suspended in phosphorus oxychloride(28 mL, 306 mmol) and heated at 80° C. for 5 hours. The solution wasevaporated in vacuo, and the residue taken up in DCM and washed withsaturated sodium bicarbonate solution until the neutral pH was observed.The organic layer was dried over magnesium sulfate and evaporated todryness. The residue was purified by silica chromatography using 1%methanol in DCM as eluent to yield 9.28 g of title compound (89%). [M+H]calc'd for C₁₇H₁₆ClN₃O₃, 346. found, 346.

5-Chloro-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (compound8D)

5-Chloro-3-(4-methoxybenzyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(8.75 g, 23.9 mmol, compound 8C) was dissolved in trifluoroacetic acid(15 mL) and subjected to microwave irradiation at 150° C. for 1 hour.TFA was evaporated in vacuo and the residue azeotroped with toluene(2×20 mL) then DCM (2×20 mL) to give 9.24 g of the title compound as acrude material which was used without further purification. [M+H] calc'dfor C₉H₈ClN₃O₂, 226. found, 226.

(R)-5-Chloro-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(compound 8E)

5-Chloro-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (8.3 g,36.8 mmol, 1 eq, compound 8D), cesium carbonate (47.9 g, 147.5 mmol, 4eq) and potassium iodide (30 mg, cat) were stirred in anhydrous DMF (180mL, 0.4 M) containing 4 Å molecular sieves (2.49 g) under N₂. After 15minutes (S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (25.1 mL, 184mmol, 5 eq) was added and the mixture stirred at 120° C. for 12 hours.DCM (150 mL) was added and the organic layer washed with water (150 mL)dried over magnesium sulfate and evaporated. The residue was purified bysilica chromatography using 0-70% EtOAc/Hexane as eluent to give 4.8 gof product. [M+H] calc'd for C₁₅H₁₈ClN₃O₄, 340. found, 340.

(R)-3-(2,3-Dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(Example 8)

(R)-5-Chloro-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(9.2 g, 27.1 mmol, 1 eq, compound 8E), 2-fluoro-4-iodoaniline (12.9 g,54.2 mmol, 2 eq), tris(dibenzylideneacetone)dipalladium(0) (1.99 g, 2.17mmol, 0.08 eq), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (1.25 g,2.17 mmol, 0.08 eq) and sodium tert-butoxide (7.81 g, 81.4 mmol, 3 eq)were heated in degassed anhydrous 1,4-dioxane (80 mL) at 100° C. for 1hour. Upon cooling, the solution was filtered and the solid washed withDCM. The filtrate was evaporated in vacuo and the residue (crude 8F) wastaken up in H₂O (20 mL) and THF (20 mL). 1N HCl (15 mL) was added andthe solution heated at 70° C. for 30 minutes. Upon cooling an off-whitesolid precipitated which was collected by filtration, washed with waterand dried. The solid was purified by HPLC to give 4.2 g of titlecompound (31%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.63(s, 3H) 3.38 (t, J=6.06 Hz, 1H) 3.41-3.51 (m, 1H) 3.61 (s, 3H) 3.62-3.68(m, 1H) 3.75 (br. s., 1H) 4.81 (t, J=5.56 Hz, 1H) 5.11 (d, J=5.31 Hz,1H) 6.60 (t, J=8.72 Hz, 1H) 7.45 (d, J=9.60 Hz, 1H) 7.66 (d, J=10.61 Hz,1H) 8.48 (s, 1H) 10.16 (s, 1H). [M+H] calc'd for C₁₈H₁₈FIN₄O₄, 501.found, 501.

Example 9(S)-5-(4-Bromo-2-fluorophenylamino)-3-(2,3-dihydroxypropyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

3-Benzyl-6-(methylamino)pyrimidin-4(3H)-one (compound 5A)

6-(Methylamino)pyrimidin-4(3H)-one (compound 1B) (3 g, 24 mmol, 1 eq),benzyl bromide (5.7 mL, 48 mmol, 2 eq) and potassium carbonate (6.96 g,50.4 mmol, 2.1 eq) were stirred in ethanol (30 mL) at RT overnight. Thesolvent was removed in vacuo and the residue purified by silicachromatography to give 2.25 g of the title compound (43%). ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.64 (d, J=4.29 Hz, 3H) 4.92-5.01 (m, 2H) 6.96 (q,J=4.63 Hz, 1H) 7.22-7.30 (m, 3H) 7.30-7.37 (m, 2H) 8.24 (s, 1H). [M+H]calc'd for C₁₂H₁₃N₃O, 216. found, 216.

3-Benzyl-5-hydroxy-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(compound 9B)

3-Benzyl-6-(methylamino)pyrimidin-4(3H)-one (compound 5A) (10 g, 46.5mmol, 1 eq) and diethyl methylmalonate (16 mL, 93 mmol, 2 eq) wereheated in phenyl ether (20 mL, 127 mmol) at 240° C. for 3 hours. Thesolution was cooled and diethyl ether (100 mL) was added. A precipitateformed which was filtered and washed with ether to give 10.5 g of thetitle compound as a tan solid (76%). [M+H] calc'd for C₁₆H₁₅N₃O₃, 298.found, 298.

3-Benzyl-5-chloro-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(compound 9C)

3-Benzyl-5-hydroxy-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(5.5 g, 18.5 mmol) was dissolved in excess POCl₃ (50 mL) and heated atreflux for 1 hour. POCl₃ was removed in vacuo and the residue dissolvedin DCM then quickly washed with saturated sodium bicarbonate solutionuntil neutral pH was observed. The organic layer was dried over MgSO₄and evaporated to dryness to give 7.3 g of the title compound as animpure reddish brown solid. [M+H] calc'd for C₁₆H₁₄ClN₃O₂, 315. found,315.

3-Benzyl-5-(2-fluoro-4-nitrophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(compound 9D)

3-Benzyl-5-chloro-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(7 g, 22.2 mmol, 1 eq), 2-fluoro-4-nitroaniline (53.8 mg, 24.4 mmol, 1.1eq), tris(dibenzylideneacetone)dipalladium(0) (407 mg, 0.44 mmol, 0.02eq), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (257 mg, 0.44 mmol,0.02 eq) and sodium tert-butoxide (3.2 g, 0.33 mmol, 1.5 eq) were mixedin degassed anhydrous dioxane (50 mL) and subjected to microwaveirradiation at 115° C. for 40 minutes. Upon cooling diethyl ether (50mL) was added. A precipitate formed which was filtered and washed withether to give 4.1 g of the title compound (42%). [M+H] calc'd forC₂₂H₁₈FN₅O₄, 436. found, 436.

5-(4-Amino-2-fluorophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(compound 9E)

3-Benzyl-5-(2-fluoro-4-nitrophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(4.1 mg, 9.42 mmol), palladium hydroxide (20% on carbon, 4 g) andammonium formate (4 g, 63.4 mmol) were stirred in dioxane (200 mL) at90° C. for 4 hours in a sealed pressure vessel. The suspension wasfiltered and the solid refluxed in DMF (20 mL) for 1 hour then filtered.This was repeated 3 times. The filtrates were combined and evaporated.The residue was dissolved in DMF (50 mL) and Quadrapure palladiumscavenger (20 g) was added and the mixture stirred at 60° C. overnight.The mixture was filtered and evaporated, ether was added and aprecipitate formed. This solid was filtered to give 2 g of the titlecompound (67%). [M+H] calc'd for C₁₅H₁₄FN₅O₂, 316. found, 316.

5-(4-Bromo-2-fluorophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(compound 9F)

5-(4-Amino-2-fluorophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(1.15 g, 3.65 mmol, 1 eq) was dissolved in a 1:1 mixture of acetic acidand water (50 ml) at 0° C. Concentrated HCl (1.6 mL) in water (2 mL) wasslowly added and the mixture stirred for 20 minutes. Sodium nitrite (252mg, 3.65 mmol, 1 eq) in water (800 μL) was added and the solutionstirred for 20 minutes. Copper(I) bromide (2.62 g, 18.2 mmol, 5 eq) wasadded and the reaction allowed to RT then stirred for 1 hour at 90° C.After cooling, the mixture was evaporated in vacuo. The residue waspurified by silica chromatography eluting with 10% methanol in DCM togive 754 mg of the title compound (54%). [M+H] calc'd for C₁₅H₁₂BrFN₄O₂,380. found, 380.

(S)-5-(4-Bromo-2-fluorophenylamino)-3-(2,3-dihydroxypropyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(Example 9)

Sodium hydride (25 mg, 1.32 mmol, 5 eq) was stirred in anhydrous DMF(200 μL) for 10 minutes.5-(4-Amino-2-fluorophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(250 mg, 0.66 mmol, 1 eq) in anhydrous DMF (100 μL) was added and themixture stirred for 10 minutes.(R)-4-(Chloromethyl)-2,2-dimethyl-1,3-dioxolane (180 μL, 1.32 mmol, 5eq) was added and the mixture subjected to microwave irradiation at 150°C. for 45 minutes. The solvent was removed in vacuo. The residue (crudecompound 9G) was taken up in H₂O (1 mL) and THF (1 mL). 1N HCl (1 mL)was added and the solution stirred at RT for 1 hour. After evaporationin vacuo the residue was purified by HPLC to give 23 mg of the titlecompound (7%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.74 (s, 3H) 3.52-3.66 (m,2H) 3.71 (s, 3H) 3.82 (dd, J=13.64, 8.34 Hz, 1H) 3.94-4.00 (m, 1H) 4.28(dd, J=13.52, 3.16 Hz, 1H) 6.74 (t, J=8.72 Hz, 1H) 7.16 (d, J=9.09 Hz,1H) 7.28 (dd, J=10.23, 2.15 Hz, 1H) 8.30 (s, 1H) 10.13 (s, 1H) [M+H]calc'd for C₁₈H₁₈BrFN₄O₄, 454. found, 454.

Example 10(R)-5-(4-Bromo-2-fluorophenylamino)-3-(2,3-dihydroxypropyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

The title compound was prepared according to the procedure used forExample 9 synthesis by reaction of(S)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane with compound 9F,followed by hydrolysis with 1N HCl. ¹H NMR (400 MHz, MeOD) δ ppm 1.71(s, 3H) 3.44-3.51 (m, 1H) 3.59 (d, J=5.31 Hz, 2H) 3.74 (s, 3H) 3.76-3.82(m, 1H) 3.91-4.01 (m, 1H) 4.41 (dd, J=13.64, 3.28 Hz, 1H) 6.77 (t,J=8.59 Hz, 1H) 7.26 (d, J=9.09 Hz, 1H) 7.39 (d, J=2.02 Hz, 1H) 8.38 (s,1H)) [M+H] calc'd for C₁₈H₁₈BrFN₄O₄, 454. found, 454.

Example 115-(4-Bromo-2-fluorophenylamino)-3-(2-hydroxyethyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

The title compound was prepared according to the procedure used forExample 9 by reaction of 2-bromoethanol with compound 9F. ¹H NMR (400MHz, MeOD) δ ppm 1.70 (s, 3H) 3.74 (s, 3H) 3.82 (t, J=5.05 Hz, 2H) 4.13(t, J=5.05 Hz, 2H) 4.53 (s, 1H) 6.78 (t, J=8.72 Hz, 1H) 7.26 (dd,J=8.21, 1.39 Hz, 1H) 7.37 (dd, J=10.48, 2.15 Hz, 1H) 10.27 (s, 1H) [M+H]calc'd for C₁₇H₁₆BrFN₄O₃, 424. found, 424.

Example 125-(2-Fluoro-4-iodophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

The title compound was synthesized from compound 9E (1.74 g, 5.5 mmol)which was first dissolved in a 1:1 mixture of acetic acid and water (10mL) at 0° C. Concentrated HCl (1.2 mL) in water (2 mL) was slowly addedand the mixture stirred for 20 minutes. Sodium nitrite (381 mg, 5.5mmol, 1 eq) in water (800 μL) was added and the solution stirred for 20minutes. Potassium iodide (4.58 g, 27.6 mmol, 5 eq) and iodine (20 mg,cat) was added and the reaction allowed to RT then stirred for 1 hour at90° C. After cooling, the mixture was evaporated in vacuo. The residuewas purified by silica chromatography eluting with 10% methanol in DCMto give 1.21 g of the title compound (51%). [M+H] calc'd forC₁₅H₁₂FIN₄O₂, 427. found, 427.

Example 13(S)-3-(2,3-Dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

Sodium hydride (67 mg, 3.5 mmol, 5 eq) was stirred in anhydrous DMF (500μL) for 10 minutes.5-(2-fluoro-4-iodophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(300 mg, 0.70 mmol, 1 eq, Example 12) in anhydrous DMF (300 μL) wasadded and the mixture stirred for 10 minutes.(R)-4-(Chloromethyl)-2,2-dimethyl-1,3-dioxolane (180 μL, 1.32 mmol, 5eq) was added and the mixture subjected to microwave irradiation at 135°C. for 1 hour. The solvent was removed in vacuo. The residue was takenup in H₂O (1 mL) and THF (1 mL). 1N HCl (1 mL) was added and thesolution stirred at RT for 1 hour. After evaporation in vacuo theresidue was purified by HPLC to give 88 mg (25%) of the title compound.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.64 (s, 3H) 2.11 (s, 3H) 3.18 (d,J=5.31 Hz, 1H) 3.32-3.42 (m, 1H) 3.63-3.70 (m, 1H) 3.70-3.82 (m, 1H)4.24-4.38 (m, 1H) 4.78 (t, J=5.56 Hz, 1H) 5.09 (d, J=5.56 Hz, 1H) 6.62(t, J=8.72 Hz, 1H) 7.45 (dd, J=7.71, 2.15 Hz, 1H) 7.66 (dd, J=10.61,2.02 Hz, 1H) 8.48 (s, 1H) 10.16 (s, 1H) [M+H] calc'd for C₁₈H₁₈FIN₄O₄,501. found, 501.

Example 145-(2-Fluoro-4-iodophenylamino)-3-(2-hydroxyethyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

The title compound was prepared according to the procedure outlined incompound 9G from the reaction of 2-bromoethanol with example 12,followed by HPLC purification. ¹H NMR (400 MHz, MeOD) δ ppm 1.71 (s, 3H)3.09-3.16 (m, 1H) 3.44-3.51 (m, 1H) 3.74 (s, 3H) 3.78-3.86 (m, 2H) 4.13(t, J=4.93 Hz, 2H) 6.62 (t, J=8.46 Hz, 1H) 7.43 (dd, J=8.34, 1.01 Hz,1H) 7.52 (dd, J=10.23, 1.89 Hz, 1H) 8.38 (s, 1H). [M+H] calc'd forC₁₇H₁₆FIN₄O₃, 471. found, 471.

Example 155-(2-Fluorophenylamino)-3-(2-hydroxyethyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

The title compound was isolated as a deiodinated byproduct from theexample 14 reaction mixture. ¹H NMR (400 MHz, MeOD) δ ppm 1.68 (s, 3H)3.45-3.51 (m, 1H) 3.74 (s, 3H) 3.78-3.89 (m, 2H) 4.13 (t, J=5.18 Hz, 2H)6.81-6.95 (m, 1H) 6.96-7.20 (m, 3H) 8.38 (s, 1H) 10.32 (s, 1H) [M+H]calc'd for C₁₇H₁₇FN₄O₃, 345. found, 345

Example 16(R)-3-(2,3-Dihydroxypropyl)-5-(4-ethynyl-2-fluorophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

(R)-3-(2,3Dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(200 mg, 0.4 mmol, Example 8), trimethylsilyl acetylene (66 μL, 0.6mmol), triethylamine (84 μL, 0.6 mmol), copper iodide (14 mg, cat) anddichlorobis(triphenylphoshine) palladium(II) (14 mg, 0.02 mmol) weremixed in THF (2 mL). The mixture was subjected to microwave irradiationat 120° C. for 20 minutes. The solvent was removed in vacuo and theresidue dissolved in methanol. Potassium carbonate (50 mg) was added andthe solution stirred at RT for 1 hour. After filtration and evaporationthe residue was purified by HPLC to give 119 mg of the title compound.¹H NMR (400 MHz, CDCl₃) δ ppm 1.79 (s, 3H) 3.11 (s, 1H) 3.54-3.66 (m,3H) 3.82-3.90 (m, 1H) 3.94-4.02 (m, 1H) 4.30 (dd, J=14.15, 3.79 Hz, 1H)6.67 (t, J=8.46 Hz, 1H) 7.19 (dd, J=8.21, 0.88 Hz, 1H) 7.21-7.25 (m, 1H)8.27 (s, 1H) [M+H] calc'd for C₂₀H₁₉FN₄O₄, 399. found, 399.

Example 176-Fluoro-5-(2-fluoro-4-iodophenylamino)-3-(2-hydroxyethyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

To a mixture of3-benzyl-5-(2-fluoro-4-nitrophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(42 mg, 0.1 mmol, 1 eq, compound 5D) in acetonitrile (1 mL) was addedSelectfluor (35 mg, 0.1 mmol, 1 eq). The reaction mixture was irradiatedwith microwave at 82° C. for 10 minutes. The solvent was removed undervacuum and the residue was purified by flash chromatography with 1:9MeOH:DCM to yield the desired product 17A (10 mg, 23% yield). [M+H]calc'd for C₂₁H₁₅F₂N₅O₄, 440. found, 440.

To a mixture of3-benzyl-6-fluoro-5-(2-fluoro-4-nitrophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione17A (1.1 g, 2.5 mmol, 1 eq) and palladium hydroxide on carbon (20%weight, 1.29 g) in 1,4-dioxane (30 mL) in a sealed tube was addedammonium formate (1.19 g, 18.8 mmol, 7.5 eq). The reaction mixture washeated at 90° C. for 1 hour. After cooling the solid was filtered offand heated in DMF at 90° C. for 30 minutes to release more product. Thisprocess was repeated until the DMF contained no more product. QuadraPureTU (1 g) was then added to the combined solution containing the productand the mixture was heated at 60° C. for 3 hours. After cooling thesolid was filtered off and the filtrate was concentrated in vacuo toyield the desired product 17B (541 mg, 68% yield). [M+H] calc'd forC₁₄H₁₁F₂N₅O₂, 320. found, 320.

To a mixture of5-(4-amino-2-fluorophenylamino)-6-fluoro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione17B (529 mg, 1.66 mmol, 1 eq) in acetic acid (5 mL) and water (5 mL) wasadded a solution of concentrated hydrochloric acid (0.7 mL) in water(0.9 mL) at 0° C. Sodium nitrite (116 mg, 1.66 mmol, 1 eq) in water wasthen added dropwise and the reaction mixture was stirred for 30 minutesat 0° C. Potassium iodide (1.4 g, 8.3 mmol, 5 eq) and iodine (17 mg) inwater were quickly added and the reaction was allowed to warm up toambient temperature, followed by heating at 70° C. for 30 minutes. Themixture was then extracted with 5%:5%:90% MeOH:DCM:H₂O and the organiclayer was concentrated in vacuo. The residue was triturated in methanoland purified by flash chromatography with 5:95 MeOH:DCM to yield thedesired product 17C (186 mg, 26% yield). [M+H] calc'd for C₁₄H₉F₂₁N₄O₂,431. found, 431.

To a mixture of6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione17C (60 mg, 0.14 mmol, 1 eq) and potassium iodide (39 mg) in DMF (3 mL)was added cesium carbonate (135 mg, 0.42 mmol, 3 eq). The reactionmixture was stirred at ambient temperature for 5 minutes. 2-Bromoethanol(0.1 mL, 1.4 mmol, 10 eq) was then added and the reaction mixture wasirradiated with microwave at 140° C. for 20 minutes. The reactionmixture was filtered and the filtrate was purified by preparatory LC/MS(30-55% CH₃CN in H₂O) to give6-fluoro-5-(2-fluoro-4-iodophenylamino)-3-(2-hydroxyethyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(example 17) as an off-white solid (25 mg, 38% yield). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 3.59 (s, 3H) 3.67 (dd, J=2.53, 1.26 Hz, 2H) 4.05 (t,J=5.05 Hz, 2H) 4.98 (br. s., 1H) 6.99 (td, J=8.65, 5.43 Hz, 1H) 7.53(dd, J=8.34, 0.76 Hz, 1H) 7.68 (dd, J=10.36, 1.77 Hz, 1H) 8.55 (s, 1H)10.22 (d, J=2.27 Hz, 1H). [M+H] calc'd for C₁₆H₁₃F₂₁N₄O₃, 475. found,475.

Example 18(R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

To a solution of(R)-3-(2,3-dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(example 6) (1 g, 2.06 mmol, 1 eq) in DMF (19 mL) was added dropwise amixture of Selectfluor (801 mg, 2.26 mmol, 1.1 eq) in acetonitrile (9mL) and DMF (5 mL) at ambient temperature while stirring under nitrogen.The reaction mixture was stirred for 10 minutes at ambient temperatureand filtered. The filtrate was purified by preparatory LC/MS (30-55%CH₃CN in H₂O) to give(R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(example 18) as an off-white solid. The recovered starting material wassubjected to the same reaction conditions to produce a second crop ofproduct. The total yield of product was 347 mg (33% yield). ¹H NMR (400MHz, DMSO-d₆) δ ppm 3.36-3.40 (m, 1H) 3.43-3.50 (m, 1H) 3.58 (s, 3H)3.61-3.72 (m, 1H) 3.72-3.82 (m, 1H) 4.27-4.37 (m, 1H) 4.78-4.87 (m, 1H)5.14 (d, J=5.81 Hz, 1H) 6.93-7.03 (m, 1H) 7.53 (d, J=8.84 Hz, 1H)7.65-7.74 (m, 1H) 8.52 (s, 1H) 10.25 (d, J=1.01 Hz, 1H). [M+H] calc'dfor C₁₇H₁₅F₂₁N₄O₄, 505. found, 505.

Example 19(S)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

To a solution of(S)-3-(2,3-dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(example 5) (1.25 g, 2.58 mmol, 1 eq) in DMF (26 mL) was added a mixtureof Selectfluor (1.187 g, 3.35 mmol, 1.3 eq) in acetonitrile (26 mL). Thereaction mixture was irradiated with microwave at 82° C. for 10 minutesand filtered. The filtrate was purified by preparatory LC/MS (30-55%CH₃CN in H₂O) to give(S)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(example 19) as an off-white solid (331 mg, 25% yield). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 3.36-3.42 (m, 1H) 3.42-3.51 (m, 1H) 3.59 (s, 3H)3.63-3.72 (m, 1H) 3.73-3.81 (m, 1H) 4.32 (dd, J=13.14, 3.03 Hz, 1H) 4.79(br. s., 1H) 5.10 (br. s., 1H) 6.98 (td, J=8.46, 5.31 Hz, 1H) 7.52 (dd,J=8.46, 1.14 Hz, 1H) 7.68 (dd, J=10.36, 1.77 Hz, 1H) 8.51 (s, 1H) 10.24(d, J=2.27 Hz, 1H). [M+H] calc'd for C₁₇H₁₅F₂₁N₄O₄, 505. found, 505.

Example 20(R)-5-(4-Bromo-2-fluorophenylamino)-3-(2,3-dihydroxypropyl)-6-fluoro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

To a mixture of5-(4-amino-2-fluorophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione5E (5 g, 16.6 mmol, 1 eq) in acetonitrile (125 mL) and water (84 mL) wasadded a solution of 1N hydrobromic acid (35 mL) at 0° C. Sodium nitrite(2.29 g, 33.2 mmol, 2 eq) in water (25 mL) was then added dropwise andthe reaction mixture was stirred for 30 minutes at 0° C. Potassiumbromide (7.14 g, 50 mmol, 3 eq) in water (16 mL) was added and thereaction was heated at 90° C. for 1 hour. The mixture was thenconcentrated in vacuo. The residue was filtered to yield the desiredsolid product 20A which was used in next step without furtherpurification. [M+H] calc'd for C₁₄H₁₀BrFN₄O₂, 365. found, 365.

To a mixture of(R)-5-(4-bromo-2-fluorophenylamino)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione20A (1.59 g, 4.37 mmol, 1 eq) and potassium iodide (50 mg) in DMF (10mL) was added cesium carbonate (2.134 g, 6.55 mmol, 1.5 eq). Thereaction mixture was stirred at ambient temperature for 5 minutes.(S)-4-(Chloromethyl)-2,2-dimethyl-1,3-dioxolane (1.8 mL, 13.1 mmol, 3eq) was then added and the reaction mixture was irradiated withmicrowave at 140° C. for 1 hour. The reaction mixture was filtered andthe filtrate was purified by preparatory LC/MS (40-90% CH₃CN in H₂O).The residue (20B) was treated with 2:1 THF:HCl (1N) at ambienttemperature overnight to yield the desired product 20C. [M+H] calc'd forC₁₇H₁₆BrFN₄O₄, 439. found, 439.

Example 20 was prepared as an off-white solid using a procedureanalogous to that described in connection with Example 19 synthesis,except that(R)-5-(4-bromo-2-fluorophenylamino)-3-(2,3-dihydroxypropyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione20C was used instead of(S)-3-(2,3-dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione.¹H NMR (400 MHz, MeOD) δ ppm 3.57 (d, 2H) 3.68 (s, 3H) 3.76 (dd,J=13.52, 8.97 Hz, 1H) 3.89-3.98 (m, 1H) 4.38 (dd, J=13.64, 3.03 Hz, 1H)7.09 (td, J=8.65, 4.67 Hz, 1H) 7.28 (dd, J=10.23, 1.64 Hz, 1H) 7.36 (dd,J=10.36, 2.27 Hz, 1H) 8.36 (s, 1H). [M+H] calc'd for C₁₇H₁₅BrF₂N₄O₄,457. found, 457.

Example 21(S)-3-(2,3-Dihydroxypropyl)-5-(4-ethynyl-2-fluorophenylamino)-6-fluoro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

To a mixture of(S)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(example 19) (42 mg, 0.08 mmol, 1 eq), triphenylphosphine (1 mg, 0.003mmol, 0.04 eq), triethylamine (0.017 mL, 0.12 mmol, 1.5 eq) anddichlorobis(triphenylphosphine)palladium(II) (3 mg, 0.004 mmol, 0.05 eq)in THF (3 mL) was added ethynyltrimethylsilane (0.018 mL, 0.12 mmol, 1.5eq). The reaction mixture was stirred at ambient temperature for 10minutes. Catalytic amount of copper(I) iodide was then added and thereaction mixture was stirred at ambient temperature overnight. Thesolvent was removed under vacuum and the residue was purified by flashchromatography with 1:9 MeOH:DCM to yield the desired product 21A. [M+H]calc'd for C₂₂H₂₄F₂N₄O₄Si, 475. found, 475.

To a mixture of(S)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-((trimethylsilyl)ethynyl)phenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione21A in THF (3 mL) was added 1M solution of TBAF (0.14 mL, 0.14 mmol,1.75 eq). The reaction mixture was stirred at ambient temperature for 1hour. The solvent was removed under vacuum and the residue was purifiedby flash chromatography with 2:8 MeOH:DCM to yield the desired product(S)-3-(2,3-dihydroxypropyl)-5-(4-ethynyl-2-fluorophenylamino)-6-fluoro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(example 21) as an off-white solid (10 mg, 30% yield). ¹H NMR (400 MHz,MeOD) δ ppm 3.54 (s, 1H) 3.60 (d, J=5.05 Hz, 2H) 3.72 (s, 3H) 3.75-3.83(m, 1H) 3.93-4.00 (m, 1H) 4.41 (dd, J=13.52, 2.91 Hz, 1H) 7.11 (td,J=8.15, 5.68 Hz, 1H) 7.21-7.29 (m, 2H) 8.40 (s, 1H). [M+H] calc'd forC₁₉H₁₆F₂N₄O₄, 403. found, 403.

Example 22(R)-3-(2,3-dihydroxypropyl)-5-(4-ethynyl-2-fluorophenylamino)-6-fluoro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

Example 22 was prepared as an off-white solid using a procedureanalogous to that described in connection with example 21, except that(R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dionewas used instead of(S)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione.¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.37-3.41 (m, 1H) 3.43-3.50 (m, 1H) 3.59(s, 3H) 3.63-3.72 (m, 1H) 3.73-3.83 (m, 1H) 4.25 (s, 1H) 4.30-4.38 (m,1H) 4.84 (t, J=5.56 Hz, 1H) 5.14 (d, J=5.56 Hz, 1H) 7.08-7.18 (m, 1H)7.29 (dd, J=8.59, 1.26 Hz, 1H) 7.43 (dd, J=11.49, 1.64 Hz, 1H) 8.53 (s,1H) 10.34 (d, J=2.02 Hz, 1H). [M+H] calc'd for C₁₉H₁₆F₂N₄O₄, 403. found,403.

Example 23(R)—N-(4-(3-(2,3-Dihydroxypropyl)-6-fluoro-8-methyl-4,7-dioxo-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidin-5-ylamino)-3-fluorophenyl)methanesulfonamide

Compound 23A was prepared using a procedure analogous to that describedin connection with compound 20B synthesis, except that5-(4-amino-2-fluorophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(5E) was used instead of5-(4-bromo-2-fluorophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(20A). [M+H] calc'd for C₂₀H₂₂FN₅O₄ 416. found, 416.

A mixture of(R)-5-(4-amino-2-fluorophenylamino)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione23A (77 mg, 0.19 mmol, 1 eq) and pyridine (3 mL) was stirred at ambienttemperature for 10 minutes. Methanesulfonyl chloride (0.021 mL, 0.19mmol, 1.45 eq) was added and the reaction mixture was stirred at ambienttemperature overnight. The solvent was removed under vacuum and theresidue was purified by preparatory LC/MS (30-55% CH₃CN in H₂O) to yieldthe desired product 23B (62 mg, 68% yield). [M+H] calc'd forC₂₁H₂₄FN₅O₆S, 494. found, 494.

Compound 23C was prepared using a procedure analogous to that describedin connection with compound 20C synthesis, except that(R)—N-(4-(3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-8-methyl-4,7-dioxo-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidin-5-ylamino)-3-fluorophenyl)methanesulfonamide(23B) was used instead of(R)-5-(4-bromo-2-fluorophenylamino)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(20B) [M+H] calc'd for C₁₈H₂₀FN₅O₆S, 454. found, 454.

(R)—N-(4-(3-(2,3-Dihydroxypropyl)-6-fluoro-8-methyl-4,7-dioxo-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidin-5-ylamino)-3-fluorophenyl)methanesulfonamide(example 23) was prepared as an off-white solid using a procedureanalogous to that described in connection with example 19 synthesis,except that(R)—N-(4-(3-(2,3-dihydroxypropyl)-8-methyl-4,7-dioxo-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidin-5-ylamino)-3-fluorophenyl)methanesulfonamide(23C) was used instead of(S)-3-(2,3-dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione.¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.04 (s, 3H) 3.45 (d, J=4.80 Hz, 1H)3.48 (d, J=4.80 Hz, 1H) 3.57 (s, 3H) 3.60-3.71 (m, 1H) 3.72-3.82 (m, 1H)4.32 (dd, J=13.01, 2.65 Hz, 1H) 6.99 (dd, J=8.59, 2.02 Hz, 1H) 7.09 (dd,J=12.38, 2.27 Hz, 1H) 7.22 (td, J=8.97, 4.55 Hz, 1H) 8.51 (s, 1H) 9.94(s, 1H) 10.20 (d, J=2.53 Hz, 1H). [M+H] calc'd for C_(1s)H₁₉F₂N₅O₆S,472. found, 472.

Example 243-(1,3-Dihydroxypropan-2-yl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

To a mixture of5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione5F (41 mg, 0.1 mmol, 1 eq) and catalytic amount of potassium iodide inDMF (1 mL) was added potassium carbonate (21 mg, 0.15 mmol, 1.5 eq). Thereaction mixture was stirred at ambient temperature for 5 minutes.1-Chloro-2,4-dinitrobenzene (22 mg, 0.11 mmol, 1.1 eq) was then addedand the reaction mixture was irradiated with microwave at 80° C. for 30minutes and then at 100° C. for 30 minutes. The reaction mixture wasfiltered and the filtrate was purified by preparatory LC/MS (50-75%CH₃CN in H₂O) to give3-(2,4-dinitrophenyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dionecompound 24A as a yellow solid (18 mg, 31% yield). ¹H NMR (400 MHz,CDCl₃) δ ppm 3.78 (s, 3H) 6.09 (s, 1H) 7.17-7.24 (m, 1H) 7.52 (d, J=8.34Hz, 2H) 7.72-7.80 (m, 1H) 8.23 (s, 1H) 8.75 (dd, J=8.46, 2.65 Hz, 1H)9.12 (d, J=2.53 Hz, 1H) 9.83 (s, 1H). [M+H] calc'd for C₂₀H₁₂FIN₆O₆,579. found, 579.

To a mixture of3-(2,4-dinitrophenyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione24A (18 mg, 0.03 mmol, 1 eq) in DMF (0.3 mL) was added2-aminopropane-1,3-diol (29 mg, 0.3 mmol, 10 eq). The reaction mixturewas heated at 80° C. for 5 hours. The solvent was removed under vacuumand the residue was purified by preparatory LC/MS (30-55% CH₃CN in H₂O)to yield3-(1,3-dihydroxypropan-2-yl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dioneExample 24 as an off-white solid (10 mg, 66% yield). ¹H NMR (400 MHz,MeOD) δ ppm 3.65 (s, 3H) 3.87-3.95 (m, 2H) 4.04 (dd, J=11.87, 7.07 Hz,2H) 4.88-4.90 (m, 1H) 5.74 (s, 1H) 7.29 (t, J=8.34 Hz, 1H) 7.57-7.69 (m,2H) 8.50 (s, 1H). [M+H] calc'd for C₁₇H₁₆FIN₄O₄, 487. found, 487.

Example 253-(1,3-Dihydroxypropan-2-yl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

Example 24 (65 mg, 0.13 mmol) was stirred in DMF (0.25 mL) at 80° C. Aslurry solution of Selectfluor® (52 mg, 0.15 mmol) in DMF/CH₃CN (1:2,0.75 mL) was added dropwise, and the reaction stirred 10 minutes.Purification by prep-HPLC gave 20.1 mg (30%) of the title compound as anoff-white solid. ¹H NMR (400 MHz, MeOD-d₄) δ ppm 10.40 (br. s., 1H) 8.49(s, 1H) 7.42-7.57 (m, 2H) 6.96 (td, J=8.72, 5.05 Hz, 1H) 4.72-4.82 (m,1H) 4.03 (dd, J=12.00, 7.20 Hz, 2H) 3.90 (dd, J=12.00, 4.80 Hz, 2H) 3.72(s, 3H). MS (ES) [m+H] calc'd for C₁₇H₁₅F₂₁N₄O₄, 505. found 505.

Example 265-(2-Fluoro-4-iodophenylamino)-3-(2-hydroxyethoxy)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

3-(2-tert-Butoxyethoxy)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione(compound 26A)

Compound 5F (250 mg, 0.61 mmol), potassium carbonate (209 mg, 1.51 mmol)and 1-chloro-2,4-dinitronbenzene (307 mg, 1.51 mmol) were stirred in DMAat 80° C. for 1.5 h. O-(2-tent-Butoxy-ethyl)-hydroxylamine was added atr.t and the reaction was stirred for 1 h at 80° C. Purification byprep-HPLC gave 43 mg (12%) of the title compound as an off-white solid.MS (ES) [m+H] calc'd for C₂₀H₂₂FIN₄O₄, 529. found 529.

5-(2-Fluoro-4-iodo-phenylamino)-3-(2-hydroxy-ethoxy)-8-methyl-3H,8H-pyrido[2,3-d]pyrimidine-4,7-dione(Example 26)

Compound 26A (43 mg, 0.081 mmol) was dissolved in TFA (0.8 mL) andstirred at r.t. for 2 hours. Purification by prep-HPLC gave 10.8 mg(29%) of the title compound as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.92 (s, 1H) 7.80 (dd, J=10.11, 2.02 Hz, 1H) 7.62 (dd,J=8.59, 1.26 Hz, 1H) 7.36 (t, J=8.46 Hz, 1H) 5.56 (s, 1H) 4.99 (br. s.,1H) 4.29-4.38 (m, 2H) 3.64-3.78 (m, 2H) 3.50 (s, 3H). MS (ES) [m+H]calc'd for C₁₆H₁₄FIN₄O₄, 473. found 473.

Example 27(R)-3-(2,3-Dihydroxypropoxy)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

Compound 5F (1.31 g, 3.17 mmol), potassium carbonate (1.1 g, 7.92 mmol)and 1-chloro-2,4-dinitronbenzene (1.60 g, 7.92 mmol) were stirred in DMAat 80° C. for 2 hours.(R)—O-((2,2-Dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (4.66 g,31.7 mmol) was added at r.t and the reaction was stirred for 1 hour at80° C. Purification by prep-HPLC gave 210 mg (13%) of the title compoundas a clear yellow solid (Deprotection occurred while concentrating thepurification fractions containing 0.5% of TFA). ¹H NMR (400 MHz,DMSO-d₆): 6 ppm 10.18 (s, 1H) 8.93 (s, 1H) 7.81 (dd, J=10.11, 1.77 Hz,1H) 7.62 (dd, J=7.58, 1.01 Hz, 1H) 7.37 (t, J=8.46 Hz, 1H) 5.56 (s, 1H)4.39 (dd, J=10.74, 3.16 Hz, 1H) 4.21 (dd, J=10.61, 7.33 Hz, 1H)3.82-3.88 (m, 1H) 3.50 (s, 3H) 3.42-3.46 (m, 2H). MS (ES) [m+H] calc'dfor C₁₇H₁₆FIN₄O₅, 503. found 503.

Example 28(R)-3-(2,3-Dihydroxypropoxy)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

Example 27 (110 mg, 0.22 mmol) was stirred in DMF (0.5 mL) at r.t. Aslurry solution of Selectfluor® (86 mg, 0.24 mmol) in DMF/CH₃CN (1:2,1.5 mL) was added dropwise at r.t., and the reaction stirred 15 minutes.Purification by prep-HPLC gave 78 mg (34%) of the title compound as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.88 (d, J=1.77 Hz, 1H)8.95 (s, 1H) 7.71 (d, J=10.11 Hz, 1H) 7.54 (d, J=8.34 Hz, 1H) 7.00 (td,J=8.65, 5.18 Hz, 1H) 5.12 (br. s., 1H) 4.74 (br. s., 1H) 4.39 (dd,J=10.36, 2.78 Hz, 1H) 4.20 (dd, J=10.48, 7.20 Hz, 1H) 3.81-3.87 (m, 1H)3.58 (s, 3H) 3.38-3.47 (m, 2H). MS (ES) [m+H] calc'd for C₁₇H₁₅F₂₁N₄O₅,521. found 521.

Example 29(R)-5-(4-Bromo-2-fluorophenylamino)-6-chloro-3-(2,3-dihydroxypropyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

Compound 20C (60 mg, 0.136 mmol) was dissolved in 2 mL DCM. NCS (22 mg,0.165 mmol) was added. The mixture was stirred at room temperatureovernight. Example 29 (35.3 mg, 54%) was isolated by preparative HPLCseparation. ¹H NMR (400 MHz, MeOD) δ 8.50 (s, 1H) 7.45 (d, J=8.0 Hz, 1H)7.38 (d, J=8.0 Hz, 1H) 7.10 (t, J=8.0 Hz, 1H) 4.51 (m, 1H) 4.03 (m, 1H)3.88 (m, 1H), 3.82 (s, 3H) 3.68 (d, J=4 Hz, 2H). [M+H] calc'd forC₁₇H₁₅BrClFN₄O₄, 475. found, 475.

Example 306-Chloro-5-(2-fluoro-4-iodophenylamino)-3-(2-hydroxyethyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

The title compound was prepared following the same procedure for thesynthesis of Example 29 using example 2 as starting material. ¹H NMR(400 MHz, CDCl₃) δ 8.20 (s, 1H) 7.49 (m, 2H) 6.75 (t, J=8.08 Hz, 1H)4.11 (t, J=5.04 Hz, 2H) 4.00 (t, J=4.0 Hz, 2H) 3.66 (s, 3H). [M+H]calc'd for C₁₆H₁₃ClFIN₄O₃, 491. found, 491.

Example 315-(2-Fluoro-4-iodophenylamino)-3-(3-hydroxypropyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

The title compound was prepared following the same procedure for thesynthesis of example 2 using 2-(3-bromopropoxy)tetrahydro-2H-pyran asstarting material instead of compound 2B. ¹H NMR (400 MHz, CDCl₃) δ 8.19(s, 1H) 7.50 (m, 2H) 7.25 (t, J=8.08 Hz, 1H) 5.92 (s, 1H) 4.19 (t,J=5.04 Hz, 2H) 3.70 (m, 2H) 3.66 (s, 3H) 2.05 (m, 2H). [M+H] calc'd forC₁₇H₁₆FIN₄O₃, 471. found, 471.

Example 326-Chloro-5-(2-fluoro-4-iodophenylamino)-3-(3-hydroxypropyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

The title compound was prepared following the same procedure for thesynthesis of example 29 using example 31 as starting material. ¹H NMR(400 MHz, CDCl₃) δ 8.21 (s, 1H) 7.44 (m, 2H) 6.74 (t, J=8.36 Hz, 1H)4.19 (t, J=6.56 Hz, 2H) 3.69 (t, J=8.0 Hz, 2H) 3.77 (s, 3H) 2.04 (m,2H). [M+H] calc'd for C₁₇H₁₅ClFIN₄O₃, 505. found, 505.

Example 335-(4-Bromo-2-fluorophenylamino)-3-(3-hydroxypropyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

The title compound was prepared following the same procedure for thesynthesis of example 2 using 2-(3-bromopropoxy)tetrahydro-2H-pyran asstarting material instead of compound 2B, and 4-bromo-2-fluoroanilineinstead of 2-fluoro-4-iodoaniline for the tosylate displacement step. ¹HNMR (400 MHz, MeOD) δ 8.48 (s, 1H) 7.42 (m, 3H) 5.70 (s, 1H) 4.15 (t,J=6.84 Hz, 2H) 3.63 (m, 5H) 2.00 (m, 2H). [M+H] calc'd forC₁₇H₁₆BrFN₄O₃, 423. found, 423.

Example 345-(4-Bromo-2-fluorophenylamino)-6-chloro-3-(3-hydroxypropyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

The title compound was prepared following the same procedure for thesynthesis of example 29 using example 33 as starting material. ¹H NMR(400 MHz, CDCl₃) δ 8.22 (s, 1H) 7.25 (m, 2H) 6.90 (t, J=8.0 Hz, 1H) 4.19(t, J=6.32 Hz, 2H) 3.77 (s, 3H) 3.70 (t, J=6.04 Hz, 2H) 2.04 (m, 2H).[M+H] calc'd for C₁₇H₁₅BrClFN₄O₃, 459. found, 459.

Example 355-(4-Bromo-2-chlorophenylamino)-3-(3-hydroxypropyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

The title compound was prepared following the same procedure for thesynthesis of example 2 using 2-(3-bromopropoxy)tetrahydro-2H-pyran asstarting material instead of compound 2B, and 4-bromo-2-chloroanilineinstead of 2-fluoro-4-iodoaniline for the tosylate displacement step. ¹HNMR (400 MHz, MeOD) δ 8.48 (s, 1H) 7.74 (s, 1H) 7.51 (m, 2H) 5.76 (s,1H) 4.15 (t, J=6.84 Hz, 2H) 3.63 (m, 5H) 2.00 (m, 2H). [M+H] calc'd forC₁₇H₁₆BrClN₄O₃, 441. found, 441.

Example 365-(4-Bromo-2-chlorophenylamino)-6-chloro-3-(3-hydroxypropyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

The title compound was prepared following the same procedure for thesynthesis of example 29 using example 35 as starting material. ¹H NMR(400 MHz, CDCl₃) δ 8.22 (s, 1H) 7.75 (s, 1H) 7.29 (d, J=8.6 Hz, 1H) 6.79(d, J=8.6 Hz, 1H) 4.20 (t, J=6.6 Hz, 2H) 3.77 (s, 3H) 3.70 (t, J=6.6 Hz,2H) 2.05 (m, 2H). [M+H] calc'd for C₁₇H₁₅BrCl₂N₄O₃, 475. found, 475.

Example 373-(2-(Dimethylamino)ethyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

The title compound was prepared following the same procedure for thesynthesis of compound 5G using compound 5F and2-bromo-N,N-dimethylethanamine hydrobromide as starting material. ¹H NMR(400 MHz, MeOD) δ 8.57 (s, 1H) 7.68 (m, 2H) 7.33 (t, J=8.36 Hz, 1H) 5.78(s, 1H) 4.51 (t, J=4.0 Hz, 2H) 3.69 (s, 3H) 3.66 (t, J=8.0 Hz, 2H) 3.09(s, 6H).

[M+H] calc'd for C₁₈H₁₉FIN₅O₂, 484. found, 484.

Example 385-(2-Fluoro-4-iodophenylamino)-3-(2-hydroxypropyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

The title compound was prepared following the same procedure for thesynthesis of Compound 5G using compound 5F and 1-bromopropan-2-ol asstarting material. ¹H NMR (400 MHz, CDCl₃) δ 8.17 (s, 1H) 7.52 (m, 2H)7.24 (t, J=8.84 Hz, 1H) 5.81 (s, 1H) 4.39 (m, 1H) 4.25 (m, 1H) 3.57 (m,4H), 1.35 (d, J=6.32 Hz, 3H). [M+H] calc'd for C₁₇H₁₆FIN₄O₃, 471. found,471.

Example 39(S)-3-(2,4-Dihydroxybutyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

The title compound was prepared following the same procedure for thesynthesis of example 2 using (S)-4-(bromomethyl)-2-phenyl-1,3-dioxane asstarting material instead of compound 2B. ¹H NMR (400 MHz, MeOD) δ 8.44(s, 1H) 7.65 (m, 2H) 7.33 (t, J=8.6 Hz, 1H) 5.79 (s, 1H) 4.39 (m, 1H)4.11 (m, 1H) 3.80 (m, 3H) 3.68 (s, 3H), 1.83 (m, 2H). [M+H] calc'd forC₁₈H₁₈FIN₄O₄, 501. found, 501.

Example 406-Chloro-5-(2-fluoro-4-iodophenylamino)-3-(2-hydroxypropyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

The title compound was prepared following the same procedure for thesynthesis of example 29 using example 38 as starting material. ¹H NMR(400 MHz, MeOD) δ 8.48 (s, 1H) 7.55 (m, 2H) 6.92 (t, J=8.84 Hz, 1H) 4.35(m, 1H) 4.15 (m, 1H) 3.81 (m, 4H), 1.32 (d, J=6.32 Hz, 3H). [M+H] calc'dfor C₁₇H₁₅ClFIN₄O₃, 505. found, 505.

Example 41(S)-5-(4-Bromo-2-fluorophenylamino)-3-(2,3-dihydroxypropyl)-6-fluoro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

Compound 20A (1 g, 2.73 mmol),(R)-4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane (2 g, 13.3 mmol), Cs₂CO₃(1.7 g, 5.43 mmol) and KI (0.45 g, 2.73 mmol) were mixed in 10 mL of DMFand microwave heated at 120° C. for 2 h. The crude reaction mixture wasfiltered to remove Cs₂CO₃ and the solvent removed under vacuum. Thecrude was purified by flash chromatography to produce compound 41A (200mg, 15%). [M+H] calc'd for C₂₀H₂₀BrFN₄O₄, 479. found, 479.

Compound 41A (100 mg, 0.21 mmol) was treated with 2:1 THF:HCl (1N) atambient temperature overnight to produce compound 41B. Compound 41B (43mg, 47%) was isolated by preparative HPLC separation. [M+H] calc'd forC₁₇H₁₆BrFN₄O₄, 439. found, 439.

Compound 41B (43 mg, 0.098 mmol), Selectfluor (31.5 mg, 0.089 mmol) weremixed in 1 mL DMF and 1 mL CH₃CN. The mixture was heated at 80° C. for10 minutes. Example 41 (10 mg, 22.3%) as obtained by preparative HPLCpurification. ¹H NMR (400 MHz, MeOD) δ 8.39 (s, 1H) 7.37 (d, J=8.0 Hz,1H) 7.30 (d, J=8.0 Hz, 1H) 7.12 (m, 1H) 4.39 (m, 1H) 3.96 (m, 1H) 3.81(m, 1H), 3.71 (s, 3H) 3.60 (d, J=4 Hz, 2H). [M+H] calc'd forC₁₇H₁₅BrF₂N₄O₄, 457. found, 457.

Example 423-Benzyl-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

The title compound was prepared following the same procedure for thesynthesis of compound 2G using compound 5C instead of compound 2F asstarting material. ¹H NMR (400 MHz, MeOD) δ 8.62 (s, 1H) 7.67 (m, 1H)7.61 (m, 1H) 7.37 (m, 6H) 5.72 (s, 1H) 5.23 (s, 2H) 3.63 (s, 3H). [M+H]calc'd for C₂₁H₁₆FIN₄O₂, 503. found, 503.

Example 433-(1,3-Dihydroxypropan-2-yl)-5-(2-fluoro-4-iodophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

The title compound was prepared following the same procedure for thesynthesis of example 24 using example 12 as starting material instead ofcompound 5F. ¹H NMR (400 MHz, MeOD) δ 8.45 (s, 1H) 7.52 (d, J=8.0 Hz,1H) 7.43 (d, J=8.0 Hz, 1H) 6.60 (t, J=8.0 Hz, 1H) 4.0 (m, 3H) 3.91 (m,2H) 3.73 (s, 3H) 1.7 (s, 3H). [M+H] calc'd for C₁₈H₁₈FIN₄O₄, 501. found,501.

Example 44(S)-3-(2,3-Dihydroxypropyl)-5-(4-ethynyl-2-fluorophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

The title compound was prepared following the same procedure for thesynthesis of example 16 by using example 13 as the starting material. ¹HNMR (400 MHz, CDCl₃) δ ppm 1.79 (s, 3H) 3.11 (s, 1H) 3.54-3.66 (m, 3H)3.82-3.90 (m, 1H) 3.94-4.02 (m, 1H) 4.30 (dd, J=14.15, 3.79 Hz, 1H) 6.67(t, J=8.46 Hz, 1H) 7.19 (dd, J=8.21, 0.88 Hz, 1H) 7.21-7.25 (m, 1H) 8.27(s, 1H) [M+H] calc'd for C₂₀H₁₉FN₄O₄, 399. found, 399

In addition to the foregoing, the above reaction schemes, and variationsthereof, can be used to prepare the following:

2-fluoro-5-(2-fluoro-4-iodophenylamino)-3,8-dimethylpyrido[2,3-d]pyrimidine- 4,7(3H,8H)-dione

5-(2-fluoro-4-iodophenylamino)-3,8- dimethyl-2-(methylamino)pyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

5-(2-fluoro-4-iodophenylamino)-2,3,8- trimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

5-(2-fluoro-4-iodophenylamino)-1,8- dimethylpyrido[2,3-d]pyrimidine-4,7(1H,8H)-dione

3-(5-(2-fluoro-4-iodophenylamino)-8-methyl-4,7-dioxo-7,8-dihydropyrido[2,3- d]pyrimidin-1(4H)-yl)propanamide

N-(2-(5-(2-fluoro-4-iodophenylamino)-8-methyl-4,7-dioxo-7,8-dihydropyrido[2,3-d]pyrimidin-1(4H)-yl)ethyl)acetamide

5-(2-fluoro-4-iodophenylamino)-1-(2- hydroxyethyl)-8-methylpyrido[2,3-d]pyrimidine-4,7(1H,8H)-dione

2-(5-(2-fluoro-4-iodophenylamino)-8-methyl-4,7-dioxo-7,8-dihydropyrido[2,3- d]pyrimidin-1(4H)-yl)-N-methylacetamide

1-ethyl-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(1H,8H)- dione

3-cyclopropyl-5-(2-fluoro-4- iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

(S)-5-(4-bromo-2-chlorophenylamino)-3-(2,3-dihydroxypropyl)-8-methylpyrido[2,3- d]pyrimidine-4,7(3H,8H)-dione

(S)-3-(2,3-dihydroxypropoxy)-5-(2- fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine- 4,7(3H,8H)-dione

3-(2-aminoethoxy)-5-(2-fluoro-4- iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

3-(3-aminopropyl)-5-(2-fluoro-4- iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

3-(2-aminoethyl)-5-(2-fluoro-4- iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

5-(2-fluoro-4-iodophenylamino)-8- methyl-3-(pyrrolidin-3-ylmethyl)pyrido[2,3-d]pyrimidine- 4,7(3H,8H)-dione

(S)-5-(2-chloro-4-iodophenylamino)-3-(2,3-dihydroxypropyl)-8-methylpyrido[2,3- d]pyrimidine-4,7(3H,8H)-dione

(S)-5-(4-bromo-2-fluorophenylamino)-3- (2,3-dihydroxypropyl)-8-methylpyrido[2,3-d]pyrimidine- 4,7(3H,8H)-dione

(S)-3-(2,3-dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-6,8-dimethylpyrido[4,3- d]pyrimidine-4,7(3H,6H)-dione

(R)-3-(2,3-dihydroxypropyl)-5-(2-fluoro- 4-iodophenylamino)-6,8-dimethylpyrido[4,3-d]pyrimidine- 4,7(3H,6H)-dione

5-(2-fluoro-4-iodophenylamino)-3-(2-hydroxyethoxy)-6,8-dimethylpyrido[4,3- d]pyrimidine-4,7(3H,6H)-dione

5-(2-fluoro-4-iodophenylamino)-3-(3-hydroxypropyl)-6,8-dimethylpyrido[4,3- d]pyrimidine-4,7(3H,6H)-dione

5-(2-fluoro-4-iodophenylamino)-3-(2-hydroxyethyl)-6,8-dimethylpyrido[4,3- d]pyrimidine-4,7(3H,6H)-dioneBiological Testing

The activity of compounds as MEK inhibitors may be assayed in vitro, invivo or in a cell line. Further, compounds according to the presentinvention may be screened for activity against one or more MEKs.Provided below are assays for activity against MEK1 and ERK1.

Purified MEK1, MEK2 and ERK1 may be obtained as follows.

For MEK1, DNA encoding residues 2-393 (del aa 32-51, S218E/S222D) of thefull-length sequence of the human enzyme may be amplified by PCR andcloned into the BamHI/XbaI sites of pFastbac (Invitrogen), whichincorporates a 6-histidine tag at the N-terminus. The deletion fromresidues 32-51, and the two mutations, S218E and S222D, may be obtainedby quick change PCR. SEQ ID NO: 1 corresponds to residues 2-393, withdeletion from residues 32-51 and mutations S218E/S222D, and with theN-terminal 6-histidine tag. SEQ ID NO: 2 is the DNA sequence that wasused to encode SEQ ID NO: 1.

For MEK2, DNA encoding residues 1-400 (S222E/S226D) of the full-lengthsequence of the human enzyme may be amplified by PCR and cloned intopFastbac (Invitrogen), which incorporates a 6-histidine tag at theN-terminus. The two mutations, S222E and S226D, may be obtained by quickchange PCR. SEQ ID NO: 3 corresponds to residues 1-400 with mutationsS222E/S226D, and with the N-terminal 6-histidine tag and SEQ. I.D. No. 4is the DNA sequence that was used to encode SEQ ID NO: 3.

For ERK1, DNA encoding residues 1-379 of the full-length sequence of thehuman enzyme may be amplified by PCR and cloned into the SmaII/SalIsites of pGEX-6p-3 (GE Healthcare), which incorporates a GST tag at theN-terminus. SEQ ID NO: 5 corresponds to residues 1-379 with theN-terminal GST tag. SEQ ID NO: 6 is the DNA sequence that was used toencode SEQ ID NO: 5.

Recombinant baculovirus incorporating the MEK1 and MEK2 constructs maybe generated by transposition using the Bac-to-Bac system (Invitrogen).High-titer viral stocks may be generated by infection of Spodopterafrugiperda Sf9 cells; the expression of recombinant protein may becarried out by infection of Spodoptera frugiperda Sf9 (Invitrogen) in 5L Wave Bioreactors (Wave Biotech).

Recombinant protein may be isolated from cellular extracts by passageover ProBond resin (Invitrogen). Partially purified extracts of all MEK1may then be further purified by high pressure liquid chromatography overa SEC2000 gel filtration resin. The purity of MEK1 and MEK2 proteins maybe determined on denaturing SDS-PAGE gel. Purified MEK1 and MEK2 maythen be concentrated to a final concentration of 3.4 mg/ml and 5.4mg/ml, respectively. The proteins may be either stored at −78° C. in abuffer containing 50 mM TRIS-HCl pH 7.6, 250 mM NaCl, 0.1 mM EDTA and0.125 mM TCEP or at −20° C. in the presence of glycerol (finalconcentration of glycerol at 50%).

Recombinant protein incorporating the ERK1 constructs may be generatedby transformation of the expression vector into an E. coli strain HD5α(Invitrogen). To express ERK1 protein, the transformated E. coli strainmay be cultured at 37° C. C until OD0.6, and then induced by adding IPTGto final concentration of 0.5 mM, and continue to culture the cellovernight at 25° C.

Recombinant ERK1 protein may be isolated from cellular extracts bypassage over Glutathione (Amersham). Partially purified extracts of ERK1may then be further purified by high pressure liquid chromatography overa BioSep SEC3000 gel filtration resin. The purity of ERK1 protein may bedetermined on denaturing SDS-PAGE gel. Purified ERK1 may then beconcentrated to a final concentration of 1.9 mg/ml. The proteins may beeither stored at −78° C. in a buffer containing 25 mM TRIS-HCl pH 7.6,150 mM NaCl, 1 mM EDTA and 0.25 mM TCEP or at −20° C. in the presence ofglycerol (final concentration of glycerol at 50%).

It should be noted that a variety of other expression systems and hostsare also suitable for the expression of MEK1 and ERK1, as would bereadily appreciated by one of skill in the art.

The inhibitory properties of compounds relative to MEK1 or MEK2 may bedetermined using a black 384-well-plate format under the followingreaction conditions: 50 mM HEPES pH 7.3, 10 mM NaCl, 10 mM MgCl₂, 0.01%Brij35, 1 nM MEK1 or 4 nM MEK2, 25 nM ERK1, 400 μM ATP, 500 nMIPTTPITTYFFFK-5FAM-COOH (FI-Erktide), and 1% DMSO. Reaction product isdetermined quantitatively by fluorescent polarization using progressiveIMAP beads from Molecular Devices.

The assay reaction may be initiated as follows: 2 μl of the mixture of1.5 μM FI-Erktide and 75 nM ERK with 2 μl of inhibitor (2 fold serialdilutions for 11 data points for each inhibitor) containing 3% DMSO wereadded to each well of the plate, followed by the addition of 2 μl of themixture of 3 nM MEK1 or 12 nM MEK2 and 1200 μM ATP to initiate thereaction (final enzyme concentration was 1 nM for MEK1 or 4 nM forMEK2). The reaction mixture may then be incubated at room temperaturefor 22 min, and quenched and developed by addition of 20 μl of 1:200dilution of progressive IMAP beads (Molecular Devices) in 80% buffer A,20% bufferB and 0.003% Tween 20. Fluorescence polarization of theresulting reaction mixtures may be measured after a 1 hour incubation atroom temperature.

IC₅₀ values may be calculated by non-linear curve fitting of thecompound concentrations and fluorescence polarization signal to thestandard IC₅₀ equation. IC₅₀ values for select compounds are given inTable 1.

TABLE 1 IC₅₀ of Exemplified Compounds against MEK1 Example IC₅₀ (MEK1,nM) 1 ≧16 2 5-15 3 ≧16 4 5-15 5 5-15 6  ≦5 7  ≦5 8  ≦5 9 ≧16 10 ≧16 11≧16 13  ≦5 14  ≦5 15 ≧16 16 5-15 17 5-15 18  ≦5 19  ≦5 20 ≧16 21 5-15 22 ≦5 23 ≧16 24 5-15 25  ≦5 26 5-15 27 5-15 28  ≦5 29 5-15 30  ≦5 31  ≦532  ≦5 33 ≧16 34 5-15 35 ≧16 36 ≧16 37 ≧16 38 ≧16 39 ≧16 40 5-15 41 5-1542 ≧16 43 5-15 44 5-15

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the compounds, compositions,kits, and methods of the present invention without departing from thespirit or scope of the invention. Thus, it is intended that the presentinvention cover the modifications and variations of this inventionprovided they come within the scope of the appended claims and theirequivalents.

What is claimed is:
 1. A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein X is selectedfrom the group consisting of halo and tosyl; X₁ is CR₆; X₅ is CR₆; R₃ isselected from the group consisting of hydrogen and aryl(C₁₋₁₀)alkylunsubstituted or substituted with one or more substituents throughavailable valencies selected from the group consisting of halo; nitro;cyano; thio having a substituent selected from the group consisting ofhydrogen and (C₁₋₁₀)alkyl; hydroxy; (C₁₋₁₀)alkoxy optionally having asubstituent selected from the group consisting of halo, nitro, cyano,hydroxy, (C₁₋₁₀)alkoxy, amino, (C₃₋₁₂)cycloalkyl, and (C₄₋₁₂)aryl;(C₄₋₁₂)aryloxy; oxycarbonyl having a substituent selected from the groupconsisting of hydrogen and (C₁₋₁₀)alkyl; aminocarbonyl itself optionallyhaving a (C₁₋₁₀)alkyl; amino optionally having a (C₁₋₁₀)alkyl;(C₁₋₁₀)alkylamino optionally having a (C₁₋₁₀)alkyl; (C₃₋₁₂)cycloalkyl;and (C₄₋₁₂)aryl optionally having a substituent selected from the groupconsisting of halo, nitro, cyano, hydroxy, (C₁₋₁₀)alkoxy, amino, and(C₃₋₁₂)cycloalkyl; R₅ is (C₁₋₆)alkyl unsubstituted or substituted withone or more substituents through available valencies selected from thegroup consisting of halo; nitro; cyano; thio having a substituentselected from the group consisting of halo; nitro; cyano; thio having asubstituent selected from the group consisting of hydrogen and(C₁₋₁₀)alkyl; hydroxy; (C₁₋₁₀)alkoxy optionally having a substituentselected from the group consisting of halo, nitro, cyano, hydroxy,(C₁₋₁₀)alkoxy, amino, (C₃₋₁₂)cycloalkyl, and (C₄₋₁₂)aryl;(C₄₋₁₂)aryloxy; oxycarbonyl having a substituent selected from the groupconsisting of hydrogen and (C₁₋₁₀)alkyl; aminocarbonyl optionally havinga (C₁₋₁₀)alkyl; amino optionally having a (C₁₋₁₀)alkyl;(C₁₋₁₀)alkylamino optionally having a (C₁₋₁₀)alkyl; and (C₄₋₁₂)aryloptionally having a substituent selected from the group consisting ofhalo, nitro, cyano, hydroxy, (C₁₋₁₀)alkoxy, amino, and(C₃₋₁₂)cycloalkyl; R₆ are each independently selected from the groupconsisting of hydrogen; halo; amino unsubstituted or substituted withone or more (C₁₋₁₀)alkyl; and (C₁₋₅)alkyl unsubstituted or substitutedwith one or more substituents through available valencies selected fromthe group consisting of halo; nitro; cyano; thio having a substituentselected from the group consisting of hydrogen and (C₁₋₁₀)alkyl;hydroxy; (C₁₋₁₀)alkoxy optionally having a substituent selected from thegroup consisting of halo, nitro, cyano, hydroxy, (C₁₋₁₀)alkoxy, amino,(C₃₋₁₂)cycloalkyl, and (C₄₋₁₂)aryl; (C₄₋₁₂)aryloxy; oxycarbonyl having asubstituent selected from the group consisting of hydrogen and(C₁₋₁₀)alkyl; aminocarbonyl optionally having a (C₁₋₁₀)alkyl; aminooptionally having a (C₁₋₁₀)alkyl; (C₁₋₁₀)alkylamino optionally having a(C₁₋₁₀)alkyl; and (C₄₋₁₂)aryl optionally having a substituent selectedfrom the group consisting of halo, nitro, cyano, hydroxy, (C₁₋₁₀)alkoxy,amino, and (C₃₋₁₂)cycloalkyl.
 2. The compound according to claim 1,wherein the R₆ on X₁ is halo.
 3. The compound according to claim 1,wherein the R₆ on X₁ is hydrogen.
 4. The compound according to any oneof claims 1 to 3, wherein X is halo.
 5. The compound according to claim4, wherein the R₆ on X₅ is halo.
 6. The compound according to claim 4,wherein the R₆ on X₅ is hydrogen.
 7. A compound according to claim 1wherein the compound is selected from the group consisting of:3,8-dimethyl-4,7-dioxo-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidin-5-yl4-methylbenzenesulfonate;3,6,8-trimethyl-4,7-dioxo-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidin-5-yl4-methylbenzenesulfonate;3-Benzyl-5-chloro-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione;5-Chloro-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione; and3-Benzyl-5-chloro-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione.